Splicing modulating antibody-drug conjugates and methods of use thereof

Abstract

The invention relates to splicing modulating antibody-drug conjugates and methods of using the same. Linker-drug compounds and antibody-drug conjugates that bind to human tumor targets are disclosed. These linker-drug compounds and antibody-drug conjugates comprise a splicing modulator drug moiety. The disclosure further relates to methods and compositions for treating neoplastic disorders by administering the antibody-drug conjugates provided herein. In some embodiments, the splicing modifier comprises a piradienolide or a piradienolide derivative.

Description

[0001] This application is a divisional application of Chinese invention patent application No. 201980036786.3 (PCT application number PCT / US2019 / 035015), whose application date is May 31, 2019 and whose invention name is “Splicing-regulating antibody-drug conjugates and methods of use thereof”.

[0002] This disclosure claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 679,672, filed June 1, 2018; U.S. Provisional Patent Application No. 62 / 679,631, filed June 1, 2018; and U.S. Provisional Patent Application No. 62 / 779,324, filed December 13, 2018; all of which are incorporated herein by reference in their entirety.

[0003] The present disclosure relates to antibody-drug conjugates (ADCs) comprising a splicing modulator and an antibody or antigen-binding fragment thereof that binds to a human oncology antigen target. The present disclosure further relates to methods and compositions that can be used to treat or diagnose cancer that expresses the target antigen and / or is amenable to treatment by disrupting RNA splicing, as well as methods for preparing these compositions.

[0004] Most protein-coding genes in the human genome are composed 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 through a process called splicing to produce mature messenger RNA (mRNA). By including different exon combinations, alternative splicing produces mRNAs that encode different protein isoforms.

[0005] RNA splicing is catalyzed by the spliceosome, a dynamic multiprotein-RNA complex composed of five small nuclear RNAs (snRNAs U1, U2, U4, U5, and U6) and associated proteins. The spliceosome assembles on 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). Increasing evidence has linked human diseases to dysregulation of RNA splicing that affects many genes (Scotti and Swanson (2016) Nat Rev Genet. 17(1):19-32).

[0006] The spliceosome is an important target in cancer biology. Several studies have now demonstrated significant changes in the splicing profile of cancer cells and the splicing factors themselves (Agrawal et al. (2018) Curr Opin Genet Dev. [New Views in Genetics and Development] 48: 67-74). Variable splicing can cause different exon inclusion / exclusion, intron retention, or the use of cryptic splice sites (Seiler et al. (2018) Cell Rep. [Cell Reports] 23 (1): 282-296). In summary, these events cause functional changes that can cause tumorigenesis or resistance to treatment (Siegfried and Karni (2018) Curr Opin Genet Dev. [New Views in Genetics and Development] 48: 16-21).

[0007] Certain natural products can bind to the SF3b spliceosomal complex. These small molecules regulate splicing by promoting intron retention and / or exon skipping (Teng et al. (2017) Nat Commun. 8:155-22). A large fraction of the resulting transcripts contain premature stop codons, triggering nonsense-mediated mRNA decay (NMD). In addition, due to the impairment of canonical splicing, canonical transcripts are greatly reduced, which may adversely affect cell function and viability. For this reason, splicing regulators have become a promising class of drugs for the treatment of cancer (Puthenveetil et al. (2016) Bioconjugate Chem. 27:1880-8).

[0008] The proto-oncogene human epidermal growth factor receptor 2 (HER2) encodes a transmembrane tyrosine kinase receptor that belongs to the human epidermal growth factor receptor (EGFR) family (King et al. (1985) Science 229:974-6). Overexpression of HER2 can constitutively activate growth factor signaling pathways, such as the PI3K-AKT-mTOR pathway, and thereby serve as an oncogenic driver for several cancer types, 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 a transformed phenotype, and because HER2 expression is primarily restricted to malignant cells, HER2 is a promising antigen for targeting certain cancers and / or delivering novel cancer therapeutics (Parakh et al. (2017) Cancer Treat Rev. 59:1-21). Additional antigens for targeted delivery of cancer therapeutics include, but are not limited to, CD138 (also known as syndecan-1) and ephrin type A receptor 2 (EPHA2).

[0009] CD138 is a cell surface heparan sulfate proteoglycan that is essential for maintaining cell morphology and interacting with the surrounding microenvironment (Akl et al. (2015) Oncotarget 6(30):28693-715; Szatmári et al. (2015) Dis Markers 2015:796052). Typically, 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). In addition, increased expression of CD138 in stromal fibroblasts is associated with angiogenesis and cancer progression (Maeda et al. (2006) Oncogene 25: 1408-12). During B cell development, CD138 expression increases, and its presence is a hallmark of plasma cells (Ribatti (2017) Immunol Lett. 188: 64-7). CD138 expression is maintained in multiple myeloma, a malignancy of plasma cells. Therefore, 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).

[0010] EPHA2 is a transmembrane glycoprotein that is abundantly overexpressed in several malignant cancer-derived cell lines and advanced cancer forms (Wykosky and Debinski (2008) Mol Cancer Ref. 6(12):1795-1806). For example, EPHA2 is strongly overexpressed in approximately 61% of GBM patient tumors (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 in both the percentage of patient tumors and the percentage of cells within tumors, and is a plasma membrane-localized receptor that internalizes upon ligand binding (Walker-Daniels et al. (2002) Mol Cancer Res. 1:79-87). Furthermore, EPHA2 expression correlates with poor prognosis, increased metastasis, and decreased survival. Therefore, EPHA2 represents another attractive antigen for targeted delivery of novel anticancer therapies due to its expression pattern, localization, and functional importance in the outcome of cancer patients.

[0011] In various embodiments, the present disclosure provides, in part, novel compounds that are biologically active against neoplastic cells. These compounds can slow, inhibit, and / or reverse tumor growth in mammals and can be used to treat human cancer patients. In various embodiments, the present disclosure provides novel antibody-drug conjugates employing these novel compounds or other functional splicing inhibitor molecules.

[0012] More specifically, in various embodiments, the present disclosure relates to antibody-drug conjugate (ADC) complexes capable of binding to and killing neoplastic cells. In various embodiments, the ADC complexes disclosed herein comprise a linker connecting a 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.

[0013] In various embodiments, the ADC complex can be represented by formula (I):

[0014] Ab-(LD) p (I)

[0015] wherein Ab is an antibody or antigen-binding fragment thereof that targets neoplastic cells or another tumor-associated target;

[0016] D is a splicing regulator;

[0017] L is a linker that covalently links Ab to D; and

[0018] p is an integer from 1 to 15.

[0019] In various embodiments, the ADC complex can be represented by formula (I):

[0020] Ab-(LD) p (I)

[0021] wherein Ab is an antibody or antigen-binding fragment thereof that targets neoplastic cells;

[0022] D is a splicing regulator having formula (II):

[0023] or a pharmaceutically acceptable salt thereof, wherein:

[0024] R 1 is selected from the group consisting of absence, hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group, a -OC(=O)-(C1-C6 alkyl) group, and -CD3;

[0025] R 3 is selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group and a -OC(=O)-(C1-C6 alkyl) group; and

[0026] R 4 、R 5 and R 8 are each independently selected from hydrogen, a hydroxyl group, an —O—(C 1 -C 6 alkyl) group, a —OC(═O)—(C 1 -C 6 alkyl) group, and a C 1 -C 6 alkyl group;

[0027] R 6 and R 7 are each independently selected from hydrogen, -OR 17 、-OC(=O)-R 17 、-OC(=O)-NR 15 R 16 , C1-C6 alkyl groups and -NR 15 R 16 ;

[0028] R 15 and R 16are each independently selected from hydrogen, R 17 、-C(=O)-R 17 and -C(=O)-OR 17 ;

[0029] R 17 is selected from hydrogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a benzyl group and a C3-C8 heterocyclyl group; and

[0030] Z is selected from

[0031] where R 1 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 15 、R 16 and R 17 Each is independently substituted by 0 to 3 groups independently selected from the following: halogen, hydroxyl group, C1-C6 alkyl group, -O-(C1-C6 alkyl) group, -NR 15 R 16 , a C3-C8 cycloalkyl group, a C1-C6 alkylhydroxyl group, a C1-C6 alkylalkoxy group, a benzyl group and a C3-C8 heterocyclyl group,

[0032] where R 6 and R 7 At least one of them is hydrogen;

[0033] and wherein L is a linker that covalently links Ab to D; and

[0034] p is an integer from 1 to 15.

[0035] In some embodiments, the antibody or antigen-binding fragment is capable of internalization into a target cell. In some embodiments, the linker is covalently linked to a splicing regulator ("LD") of formula (II), and LD has a structure of formula (II-A):

[0036] or a pharmaceutically acceptable salt thereof,

[0037] Where Z' is selected from and

[0038] wherein all other variables are as defined with respect to formula (II).

[0039] In various other embodiments, the ADC complex can be represented by Formula (I):

[0040] Ab-(LD) p (I)

[0041] wherein Ab is an antibody or antigen-binding fragment thereof that targets neoplastic cells;

[0042] D is a splicing regulator having formula (IV):

[0043] or a pharmaceutically acceptable salt thereof, wherein:

[0044] R 1 is selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group, a -OC(=O)-(C1-C6 alkyl) group and -CD3;

[0045] R 3 is selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group and a -OC(=O)-(C1-C6 alkyl) group; and

[0046] R 4 、R 5 and R 8 are each independently selected from hydrogen, a hydroxyl group, an —O—(C 1 -C 6 alkyl) group, a —OC(═O)—(C 1 -C 6 alkyl) group, and a C 1 -C 6 alkyl group;

[0047] R 6 and R 7 are each independently selected from hydrogen, -OR 17 、-OC(=O)-R 17 、-OC(=O)-NR 15 R 16 , C1-C6 alkyl groups and -NR 15 R 16 ;

[0048] R 15 and R 16 are each independently selected from hydrogen, R 17 、-C(=O)-R 17 and -C(=O)-OR 17 ;and

[0049] R 17is selected from hydrogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a benzyl group and a C3-C8 heterocyclyl group;

[0050] where R 1 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 15 、R 16 and R 17 Each is independently substituted by 0 to 3 groups independently selected from the following: halogen, hydroxyl group, C1-C6 alkyl group, -O-(C1-C6 alkyl) group, -NR 15 R 16 , a C3-C8 cycloalkyl group, a C1-C6 alkylhydroxyl group, a C1-C6 alkylalkoxy group, a benzyl group and a C3-C8 heterocyclyl group,

[0051] where R 6 and R 7 At least one of them is hydrogen;

[0052] and wherein L is a linker that covalently links Ab to D; and

[0053] p is an integer from 1 to 15.

[0054] In some embodiments, the antibody or antigen-binding fragment is capable of internalization into a target cell. In some embodiments, the linker is covalently linked to a splicing regulator ("LD"), and the LD has a structure of formula (IV-A):

[0055] or a pharmaceutically acceptable salt thereof.

[0056] In various other embodiments, the ADC complex can be represented by Formula (I):

[0057] Ab-(LD) p (I)

[0058] wherein Ab is an antibody or antigen-binding fragment thereof that targets neoplastic cells;

[0059] D is a splicing regulator having formula (VI):

[0060] or a pharmaceutically acceptable salt thereof, wherein:

[0061] R 1 and R 9Each is independently selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group, a -OC(=O)-(C1-C6 alkyl) group and -CD3;

[0062] R 3 is selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group and a -OC(=O)-(C1-C6 alkyl) group;

[0063] R 4 、R 5 and R 8 are each independently selected from hydrogen, a hydroxyl group, an —O—(C 1 -C 6 alkyl) group, a —OC(═O)—(C 1 -C 6 alkyl) group, and a C 1 -C 6 alkyl group;

[0064] R 6 and R 7 are each independently selected from hydrogen, -OR 17 、-OC(=O)-R 17 、-OC(=O)-NR 15 R 16 , C1-C6 alkyl group, -NR 15 R 16 and joints;

[0065] R 10 is selected from hydrogen, a C1-C6 alkyl group, a -C(=O)-(C1-C6 alkyl) group and -CD3;

[0066] R 15 and R 16 are each independently selected from hydrogen, R 17 、-C(=O)-R 17 and

[0067] -C(=O)-OR 17 ;

[0068] R 17 is selected from hydrogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a benzyl group and a C3-C8 heterocyclyl group; and

[0069] a is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0070] where R 1 、R3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 15 、R 16 and R 17 Each is independently substituted by 0 to 3 groups independently selected from the following: halogen, hydroxyl group, C1-C6 alkyl group, -O-(C1-C6 alkyl) group, -NR 15 R 16 , a C3-C8 cycloalkyl group, a C1-C6 alkylhydroxyl group, a C1-C6 alkylalkoxy group, a benzyl group and a C3-C8 heterocyclyl group;

[0071] where R 6 and R 7 At least one of is hydrogen; and

[0072] where R 1 and R 9 cannot both exist and not exist at the same time;

[0073] and wherein L is a linker that covalently links Ab to D; and

[0074] p is an integer from 1 to 15.

[0075] In some embodiments, the antibody or antigen-binding fragment is capable of internalization into a target cell. In some embodiments, the linker is covalently linked to a splicing regulator ("LD"), and the LD has a structure of formula (VI-A):

[0076] or a pharmaceutically acceptable salt thereof.

[0077] In various other embodiments, the ADC complex can be represented by Formula (I):

[0078] Ab-(LD) p (I)

[0079] wherein Ab is an antibody or antigen-binding fragment thereof that targets neoplastic cells;

[0080] D is a splicing regulator having formula (VIII):

[0081] or a pharmaceutically acceptable salt thereof, wherein:

[0082] R 1is selected from the group consisting of absence, hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group, a -OC(=O)-(C1-C6 alkyl) group, and -CD3;

[0083] R 3 is selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group and a -OC(=O)-(C1-C6 alkyl) group;

[0084] R 4 is selected from hydrogen, a hydroxyl group, an —O—(C 1 -C 6 alkyl) group, a —OC(═O)—(C 1 -C 6 alkyl) group, and a C 1 -C 6 alkyl group; and

[0085] R 10 selected from 3 to 10 membered carbocyclic rings and 3 to 10 membered heterocyclic rings, each of which is surrounded by 0 to 3 R a Substitute, where each R a independently selected from halogen, C1-C6 alkyl group, -O-(C1-C6)alkyl group, C1-C6 alkylalkoxy group, C1-C6 alkylhydroxyl group, -S(=O) w -(4- to 7-membered heterocyclic ring), 4- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring;

[0086] R 15 and R 16 are each independently selected from hydrogen, R 17 、-C(=O)-R 17 and -C(=O)-OR 17 ;and

[0087] R 17 is selected from hydrogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a benzyl group and a C3-C8 heterocyclyl group;

[0088] where R 1 、R 3 、R 4 、R 10 、R 15 、R 16 and R 17 Each is independently substituted by 0 to 3 groups independently selected from the following: halogen, hydroxyl group, C1-C6 alkyl group, -O-(C1-C6 alkyl) group, -NR 15 R 16, a C3-C8 cycloalkyl group, a C1-C6 alkylhydroxy group, a C1-C6 alkylalkoxy group, a benzyl group, and a C3-C8 heterocyclyl group; and

[0089] Each R a is independently substituted with 0 to 3 groups independently selected from the group consisting of halogen, hydroxyl, -NR 15 R 16 , C1-C6 alkyl group, -(C=O)-(C1-C6 alkyl) group, -(C=O)-(C1-C6 alkyl)-(C3-C 10 heterocyclyl group), -S(=O) w -(C3-C8 heterocyclyl) groups and C1-C6 alkylcarboxylic acid groups, each of which is substituted by 0, 1 or 2 groups independently selected from the group consisting of halogen, hydroxyl groups, -NR 15 R 16 and a C1-C3 alkyl group; and

[0090] w is 0, 1, or 2;

[0091] and wherein L is a linker that covalently links Ab to D; and

[0092] p is an integer from 1 to 15.

[0093] In some embodiments, the antibody or antigen-binding fragment is capable of internalization into a target cell. In some embodiments, the linker is covalently linked to a splicing regulator ("LD"), and the LD has a structure of formula (VIII-A):

[0094] or a pharmaceutically acceptable salt thereof.

[0095] In some embodiments, the splicing modulator comprises a modulator of the SF3b complex.

[0096] In some embodiments, the splicing regulator comprises pladienolide or a pladienolide derivative. In some embodiments, the splicing regulator comprises pladienolide D or a pladienolide D derivative. In some embodiments, the pladienolide D or derivative comprises D2, D1, D4, D8, D10, D11 (E7107), D20, D21, D22, D12, or D25. In some embodiments, the pladienolide D or derivative comprises D2. In some embodiments, the pladienolide D or derivative comprises D1. In some embodiments, the pladienolide D or derivative comprises D4. In some embodiments, the pladienolide D or derivative comprises D12.

[0097] In some embodiments, the pradienolide D or derivative is a zwitterionic pradienolide D or derivative. In some embodiments, the zwitterionic pradienolide D or derivative comprises D22 or D25.

[0098] In some other embodiments, the splicing modulator comprises pradienolide B or a derivative of pradienolide B. In some embodiments, the pradienolide B or derivative comprises D9, D18, D19, or D13.

[0099] In some embodiments, the splicing regulator comprises an aryl pyrrolidone. In some embodiments, the aryl pyrrolidone comprises D15, D14, D16, D17, D26, or D33. In some embodiments, the aryl pyrrolidone comprises D15. In some embodiments, the aryl pyrrolidone is a zwitterionic aryl pyrrolidone. In some embodiments, the zwitterionic aryl pyrrolidone comprises D33.

[0100] In some embodiments, the splicing regulator comprises D1:

[0101]

[0102] In some embodiments, the splicing regulator comprises D2:

[0103]

[0104] In some embodiments, the splicing regulator comprises D3:

[0105]

[0106] In some embodiments, the splicing regulator comprises D4:

[0107]

[0108] In some embodiments, the splicing regulator comprises D4':

[0109]

[0110] In some embodiments, the splicing regulator comprises D5:

[0111]

[0112] In some embodiments, the splicing regulator comprises D6:

[0113]

[0114] In some embodiments, the splicing regulator comprises D7:

[0115]

[0116] In some embodiments, the splicing regulator comprises D8:

[0117]

[0118] In some embodiments, the splicing regulator comprises D9:

[0119]

[0120] In some embodiments, the splicing regulator comprises D10:

[0121]

[0122] In some embodiments, the splicing regulator comprises D11:

[0123]

[0124] In some embodiments, the splicing regulator comprises D12:

[0125]

[0126] In some embodiments, the splicing regulator comprises D13:

[0127]

[0128] In some embodiments, the splicing regulator comprises D14:

[0129]

[0130] In some embodiments, the splicing regulator comprises D15:

[0131]

[0132] In some embodiments, the splicing regulator comprises D16:

[0133]

[0134] In some embodiments, the splicing regulator comprises D17:

[0135]

[0136] In some embodiments, the splicing regulator comprises D18:

[0137]

[0138] In some embodiments, the splicing regulator comprises D19:

[0139]

[0140] In some embodiments, the splicing regulator comprises D20:

[0141]

[0142] In some embodiments, the splicing regulator comprises D21:

[0143]

[0144] In some embodiments, the splicing regulator comprises D22:

[0145]

[0146] In some embodiments, the splicing regulator comprises D23:

[0147]

[0148] In some embodiments, the splicing regulator comprises D24:

[0149]

[0150] In some embodiments, the splicing regulator comprises D25:

[0151]

[0152] In some embodiments, the splicing regulator comprises D26:

[0153]

[0154] In some embodiments, the splicing regulator comprises D27:

[0155]

[0156] In some embodiments, the splicing regulator comprises D28:

[0157]

[0158] In some embodiments, the splicing regulator comprises D29:

[0159]

[0160] In some embodiments, the splicing regulator comprises D30:

[0161]

[0162] In some embodiments, the splicing regulator comprises D31:

[0163]

[0164] In some embodiments, the splicing regulator comprises D32:

[0165]

[0166] In some embodiments, the splicing regulator comprises D33:

[0167]

[0168] In some embodiments, the splicing regulator comprises D34:

[0169]

[0170] In some embodiments, the splicing regulator comprises D35:

[0171]

[0172] In some embodiments, the splicing modulator comprises one of the drug moieties listed in Table 7. In some embodiments, the splicing modulator comprises D1, D2, D3, D4, D4', D5, D6, D7, D8, D9, D10, D11, D12, D13, D14, D15, D16, D17, D18, D19, D20, D21, D22, D23, D24, D25, D26, D27, D28, D29, D30, D31, D32, D33, D34, and / or D35.

[0173] In some embodiments, splicing regulators are disclosed, and their use as therapeutic agents, alone or as part of an ADC. In some embodiments, the splicing regulator comprises D4, D4', D12, D15, D8, D9, D10, D13, D18, D19, D20, D21, D22, D25, or D33.

[0174] In some embodiments, the splicing regulator comprises D4 and the linker comprises MC-Val-Cit-pABC. In some embodiments, the splicing regulator comprises D4 and the linker comprises MC-β-glucuronide. In some embodiments, the splicing regulator comprises D12 and the linker comprises MC-Val-Cit-pABC. In some embodiments, the splicing regulator comprises D12 and the linker comprises MC-β-glucuronide. In some embodiments, the splicing regulator comprises D15 and the linker comprises MC-Val-Ala-pAB.

[0175] In various embodiments, the linker used in the ADC disclosed herein is stable outside the cell, such that the ADC remains intact when present in extracellular conditions, but is capable of being cleaved upon internalization into a cell (e.g., a tumor or cancer cell). In some embodiments, the splicing regulator is cleaved from the antibody or antigen-binding fragment when the ADC enters a cell expressing the antigen targeted by the antibody or antigen-binding fragment in the ADC. In some embodiments, the linker is a cleavable linker.

[0176] In some embodiments, the linker comprises a cleavable peptide portion. In some embodiments, the cleavable peptide portion can be cleaved by an enzyme. In some embodiments, the cleavable peptide portion or linker comprises an amino acid unit. In some embodiments, the amino acid unit comprises valine-citrulline ("Val-Cit" or "VC"). In some other embodiments, the amino acid unit comprises valine-alanine ("Val-Ala" or "VA"). In some other embodiments, the amino acid unit comprises glutamic acid-valine-citrulline ("Glu-Val-Cit" or "EVC"). In some other embodiments, the amino acid unit comprises alanine-alanine-asparagine ("Ala-Ala-Asn" or "AAN").

[0177] In some embodiments, the linker comprises a cleavable glucuronide moiety. In some embodiments, the cleavable glucuronide moiety is cleavable by an enzyme. In some embodiments, the cleavable glucuronide moiety is cleavable by a glucuronidase. In some embodiments, the cleavable glucuronide moiety is cleavable by a β-glucuronidase.

[0178] In some embodiments, the linker comprises at least one spacer unit. In some embodiments, the spacer unit or 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 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.

[0179] 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.

[0180] In some embodiments, the linker comprises the Mal-spacer unit and a cleavable peptide portion. In some embodiments, the cleavable peptide portion comprises an amino acid unit. In some embodiments, the cleavable peptide portion or amino acid unit comprises Val-Cit. In some embodiments, the cleavable peptide portion or amino acid unit comprises Val-Ala. In some embodiments, the cleavable peptide portion or amino acid unit comprises Glu-Val-Cit. In some embodiments, the cleavable peptide portion or amino acid unit comprises Ala-Ala-Asn. In some embodiments, the Mal-spacer unit comprises an alkyl portion. In some embodiments, the Mal-spacer unit comprises a PEG portion. In some embodiments, the Mal-spacer unit comprises maleimidocaproyl (MC).

[0181] In some embodiments, the Mal-spacer unit connects the antibody or antigen-binding fragment to the cleavable portion in the linker. In some embodiments, the cleavable portion in the linker comprises a cleavable peptide portion. In some embodiments, the cleavable peptide portion comprises an amino acid unit. In some embodiments, the cleavable peptide portion or amino acid unit comprises 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 unit comprises an alkyl portion. In some embodiments, the Mal-spacer unit comprises a PEG portion. In some embodiments, the Mal-spacer unit comprises maleimidocaproyl (MC).

[0182] In some embodiments, the cleavable portion of the linker is directly attached to the splicing regulator, or the spacer unit connects the cleavable portion of the linker to the splicing regulator. In some embodiments, cleavage of the conjugate releases the splicing regulator from the antibody or antigen-binding fragment and the linker. In some embodiments, the spacer unit connecting the cleavable portion of the linker to the splicing regulator is self-immolative.

[0183] In some embodiments, the spacer unit that connects the cleavable portion in the linker to the splicing regulator comprises p-aminobenzyloxycarbonyl (pABC). In some embodiments, pABC connects the cleavable portion in the linker to the splicing regulator. In some embodiments, the cleavable portion in the linker comprises a cleavable peptide portion. In some embodiments, the cleavable peptide portion comprises an amino acid unit. In some embodiments, the cleavable peptide portion or amino acid unit comprises 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.

[0184] In some embodiments, the spacer unit that connects the cleavable portion of the linker to the splicing regulator comprises a p-aminobenzyl group (pAB). In some embodiments, pAB connects the cleavable portion of the linker to the splicing regulator. In some embodiments, the cleavable portion of the linker comprises a cleavable peptide portion. In some embodiments, the cleavable peptide portion comprises an amino acid unit. In some embodiments, the cleavable peptide portion or amino acid unit comprises Val-Cit, Val-Ala, Glu-Val-Cit, or Ala-Ala-Asn. In some embodiments, the linker comprises Val-Cit-pAB. In some other embodiments, the linker comprises Val-Ala-pAB. In some other embodiments, the linker comprises Glu-Val-Cit-pAB. In some other embodiments, the linker comprises Ala-Ala-Asn-pAB.

[0185] In various embodiments, the linker is a non-cleavable linker. In some embodiments, the splicing regulator in the ADC is released by degradation of the antibody or antigen-binding fragment. In some embodiments, when internalized by a target cell and degraded within the target cell, the linker remains covalently associated with at least one amino acid of the antibody and the drug.

[0186] In some embodiments, the linker is a non-cleavable linker comprising at least one spacer unit. In some embodiments, the spacer unit or 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 linker comprises an alkyl moiety. In some embodiments, the alkyl moiety comprises -(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.

[0187] In some embodiments, the spacer unit in the non-cleavable linker is connected to the antibody or antigen-binding fragment via a maleimide (Mal) portion ("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 attached 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 portion. In some embodiments, the Mal-spacer unit comprises a PEG portion. 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 splicing regulator.

[0188] In various embodiments, the ADC complex can be represented by formula (I):

[0189] Ab-(LD) p (I)

[0190] wherein Ab is an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or binding domain sequences disclosed herein) that targets a neoplastic cell or another tumor-associated target (e.g., a cancer antigen); D is any small molecule suitable for treating cancer (e.g., a splicing regulator, e.g., any of the splicing regulators disclosed herein); L is a linker that covalently links Ab to D (e.g., any of the linkers disclosed herein); and p is an integer from 1 to 15.

[0191] In some embodiments, the Ab is selected from any of the antibodies or binding domain sequences disclosed herein. In some embodiments, the Ab is an antibody or binding domain sequence that targets HER2 and / or neoplastic cells expressing HER2. In some embodiments, the Ab is an antibody or binding domain sequence that targets CD138 and / or neoplastic cells expressing CD138. In some embodiments, the Ab is an antibody or binding domain sequence that targets EPHA2 and / or neoplastic cells expressing EPHA2. In some embodiments, the Ab is an antibody or binding domain sequence that targets MSLN and / or neoplastic cells expressing MSLN. In some embodiments, the Ab is an antibody or binding domain sequence that targets FOLH1 and / or neoplastic cells expressing FOLH1. In some embodiments, the Ab is an antibody or binding domain sequence that targets CDH6 and / or neoplastic cells expressing CDH6. In some embodiments, the Ab is an antibody or binding domain sequence that targets CEACAM5 and / or neoplastic cells expressing CEACAM5. In some embodiments, the Ab is an antibody or binding domain sequence that targets CFC1B and / or neoplastic cells expressing CFC1B. In some embodiments, the Ab is an antibody or binding domain sequence that targets ENPP3 and / or neoplastic cells expressing ENPP3. In some embodiments, the Ab is an antibody or binding domain sequence that targets FOLR1 and / or neoplastic cells expressing FOLR1. In some embodiments, the Ab is an antibody or binding domain sequence that targets HAVCR1 and / or neoplastic cells expressing HAVCR1. In some embodiments, the Ab is an antibody or binding domain sequence that targets KIT and / or neoplastic cells expressing KIT. In some embodiments, the Ab is an antibody or binding domain sequence that targets MET and / or neoplastic cells expressing MET. In some embodiments, the Ab is an antibody or binding domain sequence that targets MUC16 and / or neoplastic cells expressing MUC16. In some embodiments, the Ab is an antibody or binding domain sequence that targets SLC39A6 and / or neoplastic cells expressing SLC39A6. In some embodiments, the Ab is an antibody or binding domain sequence that targets SLC44A4 and / or neoplastic cells expressing SLC44A4. In some embodiments, the Ab is an antibody or binding domain sequence that targets STEAP1 and / or neoplastic cells expressing STEAP1. In some embodiments, the Ab is an antibody or binding domain sequence that targets another cancer antigen.

[0192] In some embodiments, D is a splicing regulator. In some embodiments, D is selected from any one of the splicing regulators disclosed herein. In some embodiments, D is a splicing regulator selected from the following: D2, D1, D4, D8, D10, D11 (E7107), D20, D21, D22, D12, D25, D9, D18, D19, D13, D15, D14, D16, D17, D26, and D33, or any derivative thereof. In some embodiments, D is a splicing regulator selected from the following: D4, D12, D15, D8, D9, D10, D13, D18, D19, D20, D21, D22, D25, and D33, or any derivative thereof. In some embodiments, D is a splicing regulator comprising D2 or any derivative thereof. In some embodiments, D is a splicing regulator comprising D1 or any derivative thereof.

[0193] In some embodiments, L is selected from any one 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 units. 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, ADL21, ADL23, or ADL15 linker. In some embodiments, L is an ADL12, ADL14, or ADL15 linker. In some embodiments, an ADL1, ADL2, ADL5, ADL6, ADL7, ADL12, ADL13, ADL14, ADL21, ADL23, or ADL15 linker may further comprise one or more additional spacer units. In some embodiments, L is an ADL1 linker and may optionally comprise one or more additional spacer units. In some embodiments, L is an ADL2 linker and may optionally comprise one or more additional spacer units. In some embodiments, L is an ADL5 linker and may optionally comprise one or more additional spacer units. In some embodiments, L is an ADL6 linker and may optionally comprise one or more additional spacer units. In some embodiments, L is an ADL7 linker and may optionally comprise one or more additional spacer units. In some embodiments, L is an ADL12 linker and may optionally comprise one or more additional spacer units. In some embodiments, L is an ADL14 linker and may optionally comprise one or more additional spacer units. In some embodiments, L is an ADL15 linker and may optionally comprise one or more additional spacer units. In various embodiments of the ADC described herein, p is 1 to 10. In various embodiments, p is 2 to 8. In various embodiments, p is 4 to 8. In some embodiments, p is 4. In some embodiments, p is 8.

[0194] In some embodiments, the LD of formula (I) is ADL1-D1. In some embodiments, the LD of formula (I) is ADL6-D1. In some embodiments, the LD of formula (I) is ADL5-D2. In some embodiments, the LD of formula (I) is ADL1-D18. In some embodiments, the LD of formula (I) is ADL5-D19. In some embodiments, the LD of formula (I) is ADL14-D1. In some embodiments, the LD of formula (I) is ADL12-D1. In some embodiments, the LD of formula (I) is ADL15-D1. In some embodiments, the LD of formula (I) is ADL12-D20. In some embodiments, the LD of formula (I) is ADL10-D1. In some embodiments, the LD of formula (I) is ADL12-D2. In some embodiments, the LD of formula (I) is ADL15-D2. In some embodiments, the LD of formula (I) is ADL12-D21. In some embodiments, the LD of formula (I) is ADL6-D9. In some embodiments, the LD of formula (I) is ADL1-D4. In some embodiments, the LD of formula (I) is ADL1-D3. In some embodiments, the LD of formula (I) is ADL1-D12. In some embodiments, the LD of formula (I) is ADL1-D7. In some embodiments, the LD of formula (I) is ADL1-D6. In some embodiments, the LD of formula (I) is ADL1-D5. In some embodiments, the LD of formula (I) is ADL22-D4. In some embodiments, the LD of formula (I) is ADL5-D10. In some embodiments, the LD of formula (I) is ADL5-D11. In some embodiments, the LD of formula (I) is ADL1-D13. In some embodiments, the LD of formula (I) is ADL1-D8. In some embodiments, the LD of formula (I) is ADL1-D22. In some embodiments, the LD of formula (I) is ADL5-D25. In some embodiments, the LD of formula (I) is ADL12-D22. In some embodiments, the LD of formula (I) is ADL5-D15. In some embodiments, the LD of formula (I) is ADL1-D14. In some embodiments, the LD of formula (I) is ADL5-D26. In some embodiments, the LD of formula (I) is ADL1-D16. In some embodiments, the LD of formula (I) is ADL5-D17. In some embodiments, the LD of formula (I) is ADL1-D33. In some embodiments, the LD of formula (I) is ADL1-D28. In some embodiments, the LD of formula (I) is ADL1-D31.In some embodiments, the LD of formula (I) is ADL1-D29. In some embodiments, the LD of formula (I) is ADL1-D35. In some embodiments, the LD of formula (I) is ADL5-D32. In some embodiments, the LD of formula (I) is ADL5-D27. In some embodiments, the LD of formula (I) is ADL12-D35. In some embodiments, the LD of formula (I) is ADL12-D28. In some embodiments, the LD of formula (I) is ADL1-D23. In some embodiments, the LD of formula (I) is ADL1-D24.

[0195] In some embodiments, a pool of ADCs is provided, whereby random conjugation occurs, and the average p in the pool is between about 2 and about 8. In some embodiments, a pool of ADCs is provided, whereby random conjugation occurs, and the average p in the pool is between about 4 and about 8. In some embodiments, a pool of ADCs is provided, whereby random conjugation occurs, and the average p in the pool is about 4. In some embodiments, a pool of ADCs is provided, whereby random conjugation occurs, and the average p in the pool is about 8. Provided herein are compositions (e.g., pharmaceutical compositions) comprising multiple copies of any of the described ADCs, wherein the average drug loading (average p) of the ADCs in the composition is about 3.5 to about 5.5 (e.g., about 4), or about 7 to about 9 (e.g., about 8).

[0196] In certain embodiments, the antibody or antigen-binding fragment (Ab) in the ADC targets the neoplastic cells derived from hematological malignancies or solid tumors. In certain embodiments, the antibody or antigen-binding fragment targets the neoplastic cells derived from hematological malignancies. In certain embodiments, the hematological malignancies are selected from B cell malignancies, leukemias (e.g., acute myeloid leukemia), lymphomas, and myelomas (e.g., multiple myeloma). In certain embodiments, the hematological malignancies are selected from acute myeloid leukemia and multiple myeloma. In certain embodiments, the antibody or antigen-binding fragment targets the neoplastic cells derived from solid tumors. In certain 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, colon cancer, cervical cancer, pancreatic cancer, renal cancer, colorectal cancer, and esophageal cancer. In certain embodiments, the solid tumor is selected from HER2-positive breast cancer, gastric adenocarcinoma, prostate cancer, and osteosarcoma.

[0197] In various embodiments, the antibody or antigen binding fragment (Ab) in 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 expressing HER2 (i.e., the ADC targets neoplastic cells expressing HER2). In some embodiments, the antibody or antigen binding fragment in the ADC is an internalizing anti-HER2 antibody or an internalizing antigen binding fragment thereof.

[0198] In some embodiments, the anti-HER2 antibody or antigen-binding fragment comprises three heavy chain complementary determining regions (HCDR1, HCDR2, and HCDR3) comprising 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 complementary determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of 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 comprising the amino acid sequence of SEQ ID NO: 19 and a light chain variable region comprising the amino acid sequence of 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 for binding with and / or binds to the same epitope as an antibody comprising a heavy chain variable domain of SEQ ID NO: 19 and a light chain variable domain of SEQ ID NO: 20.

[0199] In various embodiments, the antibody or antigen binding fragment (Ab) in the ADC is an anti-CD138 antibody or antigen binding fragment thereof. In some embodiments, the antibody or antigen binding fragment binds to CD138 and targets neoplastic cells expressing CD138 (i.e., the ADC targets neoplastic cells expressing CD138). In some embodiments, the antibody or antigen binding fragment in the ADC is an internalizing anti-CD138 antibody or an internalizing antigen binding fragment thereof.

[0200] In some embodiments, the anti-CD138 antibody or antigen-binding fragment comprises three heavy chain complementary determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO: 7 (HCDR1), SEQ ID NO: 8 (HCDR2), and SEQ ID NO: 9 (HCDR3); and three light chain complementary determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of 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 human framework sequences. In some embodiments, the anti-CD138 antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 21 and a light chain variable region comprising the amino acid sequence of 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 Ig kappa 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 Ig kappa or lambda light chain constant region. In some embodiments, the anti-CD138 antibody or antigen-binding fragment competes for binding and / or binds to the same epitope as an antibody comprising a heavy chain variable domain of SEQ ID NO: 21 and a light chain variable domain of SEQ ID NO: 22.

[0201] In various embodiments, the antibody or antigen-binding fragment (Ab) in the ADC is an anti-EPHA2 antibody or antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding fragment binds to EPHA2 and targets neoplastic cells expressing EPHA2 (i.e., the ADC targets neoplastic cells expressing EPHA2). In some embodiments, the antibody or antigen-binding fragment in the ADC is an internalizing anti-EPHA2 antibody or internalizing antigen-binding fragment thereof.

[0202] In some embodiments, the anti-EPHA2 antibody or antigen-binding fragment comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of 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) comprising the amino acid sequences of 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 human framework sequences. In some embodiments, the anti-EPHA2 antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 23 and a light chain variable region comprising the amino acid sequence of 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 Ig kappa or lambda light chain constant region. In some embodiments, the anti-EPHA2 antibody or antigen-binding fragment competes for binding with and / or binds to the same epitope as an antibody comprising a heavy chain variable domain of SEQ ID NO: 23 and a light chain variable domain of SEQ ID NO: 24.

[0203] In various embodiments, provided herein are compounds comprising a linker-drug defined by the general formula: LD, wherein L = linker moiety, and D = drug moiety (e.g., splicing modulator drug moiety). In various embodiments, the linker-drug (LD) compounds disclosed herein can be linked to an antibody or antigen-binding fragment and / or be suitable for use in an ADC disclosed herein, e.g., an ADC having formula (I).

[0204] In various embodiments, the linker-drug (LD) compounds disclosed herein comprise a linker-drug structure according to formula (III). In various embodiments, the disclosure provides linker-drug (LD) compounds having formula (III):

[0205] or a pharmaceutically acceptable salt thereof, wherein:

[0206] R 1is selected from the group consisting of absence, hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group, a -OC(=O)-(C1-C6 alkyl) group, and -CD3;

[0207] R 2 Not present or a joint;

[0208] R 3 is selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group and a -OC(=O)-(C1-C6 alkyl) group; and

[0209] R 4 、R 5 and R 8 are each independently selected from hydrogen, a hydroxyl group, an —O—(C 1 -C 6 alkyl) group, a —OC(═O)—(C 1 -C 6 alkyl) group, and a C 1 -C 6 alkyl group;

[0210] R 6 and R 7 are each independently selected from hydrogen, -OR 17 、-OC(=O)-R 17 、-OC(=O)-NR 15 R 16 , C1-C6 alkyl group, -NR 15 R 16 and joints;

[0211] R 15 and R 16 are each independently selected from hydrogen, R 17 、-C(=O)-R 17 and

[0212] -C(=O)-OR 17 ;

[0213] R 17 is selected from hydrogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a benzyl group and a C3-C8 heterocyclyl group; and

[0214] Z" is selected from

[0215] where R 1 、R 2 、R 3、R 4 、R 5 、R 6 、R 7 、R 8 、R 15 、R 16 and R 17 Each is independently substituted by 0 to 3 groups independently selected from the following: halogen, hydroxyl group, C1-C6 alkyl, -O-(C1-C6 alkyl) group, -NR 15 R 16 , a C3-C8 cycloalkyl group, a C1-C6 alkylhydroxyl group, a C1-C6 alkylalkoxy group, a benzyl group and a C3-C8 heterocyclyl group;

[0216] where R 6 and R 7 At least one of is hydrogen; and

[0217] If R 2 is a connector, then R 6 and R 7 are not joints, and if R 6 or R 7 is a connector, then R 2 Does not exist.

[0218] In various other embodiments, the linker-drug (LD) compounds disclosed herein comprise a linker-drug structure according to formula (V). In various embodiments, the disclosure provides linker-drug (LD) compounds having formula (V):

[0219] or a pharmaceutically acceptable salt thereof, wherein:

[0220] R 1 is selected from the group consisting of absence, hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group, a -OC(=O)-(C1-C6 alkyl) group, and -CD3;

[0221] R 2 Not present or a joint;

[0222] R 3 is selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group and a -OC(=O)-(C1-C6 alkyl) group; and

[0223] R 4 、R 5 and R 8 are each independently selected from hydrogen, a hydroxyl group, an —O—(C 1 -C 6 alkyl) group, a —OC(═O)—(C 1 -C 6 alkyl) group, and a C 1 -C 6 alkyl group;

[0224] R 6 and R 7 are each independently selected from hydrogen, -OR 17 、-OC(=O)-R 17 、-OC(=O)-NR 15 R 16 , C1-C6 alkyl group, -NR 15 R 16 and joints;

[0225] R 15 and R 16 are each independently selected from hydrogen, R 17 、-C(=O)-R 17 and -C(=O)-OR 17 ;and

[0226] R 17 is selected from hydrogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a benzyl group and a C3-C8 heterocyclyl group;

[0227] where R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 15 、R 16 and R 17 Each is independently substituted by 0 to 3 groups independently selected from the following: halogen, hydroxyl group, C1-C6 alkyl, -O-(C1-C6 alkyl) group, -NR 15 R 16 , a C3-C8 cycloalkyl group, a C1-C6 alkylhydroxyl group, a C1-C6 alkylalkoxy group, a benzyl group and a C3-C8 heterocyclyl group;

[0228] where R 6 and R 7 At least one of is hydrogen; and

[0229] If R 2 is a connector, then R 6 and R 7 are not joints, and if R6 or R 7 is a connector, then R 2 Does not exist.

[0230] In various other embodiments, the linker-drug (LD) compounds disclosed herein comprise a linker-drug structure according to formula (VII). In various embodiments, the disclosure provides a linker-drug (LD) compound having formula (VII):

[0231] or a pharmaceutically acceptable salt thereof, wherein:

[0232] R 1 and R 9 Each is independently selected from the group consisting of absence, hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group, a -OC(=O)-(C1-C6 alkyl) group, and -CD3;

[0233] R 2 Not present or a joint;

[0234] R 3 is selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group and a -OC(=O)-(C1-C6 alkyl) group;

[0235] R 4 、R 5 and R 8 are each independently selected from hydrogen, a hydroxyl group, an —O—(C 1 -C 6 alkyl) group, a —OC(═O)—(C 1 -C 6 alkyl) group, and a C 1 -C 6 alkyl group;

[0236] R 6 and R 7 are each independently selected from hydrogen, -OR 17 、-OC(=O)-R 17 、-OC(=O)-NR 15 R 16 , C1-C6 alkyl group, -NR 15 R 16 and joints;

[0237] R 10 is selected from hydrogen, a C1-C6 alkyl group, a -C(=O)-(C1-C6 alkyl) group and -CD3;

[0238] R 15 and R 16 are each independently selected from hydrogen, R 17 、-C(=O)-R 17 and

[0239] -C(=O)-OR 17 ;

[0240] R 17 is selected from hydrogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a benzyl group and a C3-C8 heterocyclyl group; and

[0241] a is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0242] where R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 15 、R 16 and R 17 Each is independently substituted by 0 to 3 groups independently selected from the following: halogen, hydroxyl group, C1-C6 alkyl group, -O-(C1-C6 alkyl) group, -NR 15 R 16 , a C3-C8 cycloalkyl group, a C1-C6 alkylhydroxyl group, a C1-C6 alkylalkoxy group, a benzyl group and a C3-C8 heterocyclyl group;

[0243] where R 6 and R 7 At least one of them is hydrogen;

[0244] If R 2 is a connector, then R 6 and R 7 are not joints, and if R 6 or R 7 is a connector, then R 2 does not exist; and

[0245] where R 1 and R 9 Cannot exist at the same time.

[0246] In various other embodiments, the linker-drug (LD) compounds disclosed herein comprise a linker-drug structure according to formula (IX). In various embodiments, the disclosure provides linker-drug (LD) compounds having formula (IX):

[0247] or a pharmaceutically acceptable salt thereof, wherein:

[0248] R 1 is selected from the group consisting of absence, hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group, a -OC(=O)-(C1-C6 alkyl) group, and -CD3;

[0249] R 2 It is a joint;

[0250] R 3 is selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group and a -OC(=O)-(C1-C6 alkyl) group;

[0251] R 4 is selected from hydrogen, a hydroxyl group, an —O—(C 1 -C 6 alkyl) group, a —OC(═O)—(C 1 -C 6 alkyl) group, and a C 1 -C 6 alkyl group;

[0252] R 10 selected from 3 to 10 membered carbocyclic rings and 3 to 10 membered heterocyclic rings, each of which is surrounded by 0 to 3 R a Substitute, where each R a independently selected from halogen, C1-C6 alkyl group, -O-(C1-C6)alkyl group, C1-C6 alkylalkoxy group, C1-C6 alkylhydroxyl group, -S(=O) w -(4- to 7-membered heterocyclic ring), 4- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring;

[0253] R 15 and R 16 are each independently selected from hydrogen, R 17 、-C(=O)-R 17 and -C(=O)-OR 17 ;and

[0254] R 17 is selected from hydrogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a benzyl group and a C3-C8 heterocyclyl group;

[0255] where R 1 、R 2 、R 3 、R 4 、R 10 、R 15 、R 16 and R 17 Each is independently substituted by 0 to 3 groups independently selected from the following: halogen, hydroxyl group, C1-C6 alkyl group, -O-(C1-C6 alkyl) group, -NR 15 R 16 , a C3-C8 cycloalkyl group, a C1-C6 alkylhydroxy group, a C1-C6 alkylalkoxy group, a benzyl group, and a C3-C8 heterocyclyl group; and

[0256] Each R a is independently substituted with 0 to 3 groups independently selected from the group consisting of halogen, hydroxyl, -NR 15 R 16 , C1-C6 alkyl group, -(C=O)-(C1-C6 alkyl) group, -(C=O)-(C1-C6 alkyl)-(C3-C 10 heterocyclyl) group and C1-C6 alkylcarboxylic acid group, each of which is substituted by 0, 1 or 2 groups independently selected from the following: halogen, hydroxyl group, -NR 15 R 16 and a C1-C3 alkyl group; and

[0257] w is 0, 1, or 2.

[0258] In addition, in various embodiments, provided herein are therapeutic uses of the ADC complexes and compositions, for example, in the treatment of neoplastic disorders (e.g., cancer). In certain aspects, the disclosure provides methods for treating neoplastic disorders, such as cancers that express an antigen targeted by the antibody or antigen-binding fragment in the ADC, such as HER2, CD138, EPHA2, MSLN, FOLH1, CDH6, CEACAM5, CFC1B, ENPP3, FOLR1, HAVCR1, KIT, MET, MUC16, SLC39A6, SLC44A4, or STEAP1.

[0259] In certain aspects, the disclosure provides a method for treating a subject suffering from or suspected of having a neoplastic disorder by administering to the subject any of the ADC or compositions of a therapeutically effective amount and / or regimen. In some embodiments, the neoplastic disorder is a hematological malignancy or a solid tumor. In some embodiments, the neoplastic disorder is a hematological malignancy. In some embodiments, the hematological malignancy is selected from B cell malignancies, leukemias, lymphomas, and myelomas. In some embodiments, the hematological 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, colon 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.

[0260] 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.

[0261] In some embodiments, the target antigen is HER2. In some embodiments, the one or more neoplastic cells are derived from 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 that expresses HER2. 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 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.

[0262] In some embodiments, the target antigen is CD138. In some embodiments, the one or more neoplastic cells are derived from a multiple myeloma expressing CD138. In some embodiments, the subject is unresponsive or responds poorly to treatment with (a) an anti-CD138 antibody when administered alone and / or (b) a splicing regulator when administered alone. In some embodiments, the subject is intolerant, unresponsive, or responds poorly to treatment with a splicing regulator when administered alone.

[0263] In some embodiments, the target antigen is EPHA2. In some embodiments, the one or more neoplastic cells are derived from breast cancer, prostate cancer, ovarian cancer, lung cancer, melanoma, colon cancer, or esophageal cancer that expresses EPHA2. In some embodiments, the subject is unresponsive or responds poorly to treatment with (a) an anti-EPHA2 antibody when administered alone and / or (b) a splicing modulator when administered alone. In some embodiments, the subject is intolerant, unresponsive, or responds poorly to treatment with a splicing modulator when administered alone.

[0264] In some embodiments, the target antigen is MSLN. In some embodiments, the one or more neoplastic cells are derived from ovarian cancer, cervical cancer, pancreatic cancer, or lung cancer (e.g., lung adenocarcinoma) that expresses MSLN. 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.

[0265] In some embodiments, the target antigen is FOLH1. In some embodiments, the one or more neoplastic cells are derived from a prostate cancer expressing FOLH1. 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.

[0266] In some embodiments, the target antigen is CDH6. In some embodiments, the one or more neoplastic cells are derived from a renal cancer expressing CDH6. In some embodiments, the subject is unresponsive or responds poorly 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 responds poorly to treatment with a splicing regulator when administered alone.

[0267] In some embodiments, the target antigen is CEACAM5. In some embodiments, the one or more neoplastic cells are derived from a colorectal cancer expressing CEACAM5. 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 modulator when administered alone. In some embodiments, the subject is intolerant, unresponsive, or poorly responsive to treatment with a splicing modulator when administered alone.

[0268] In some embodiments, the target antigen is CFC1B. In some embodiments, the one or more neoplastic cells are derived from a pancreatic cancer expressing CFC1B. 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 modulator when administered alone. In some embodiments, the subject is intolerant, unresponsive, or poorly responsive to treatment with a splicing modulator when administered alone.

[0269] In some embodiments, the target antigen is ENPP3. In some embodiments, the one or more neoplastic cells are derived from a renal cancer expressing ENPP3. In some embodiments, the subject is unresponsive or responds poorly 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 responds poorly to treatment with a splicing regulator when administered alone.

[0270] In some embodiments, the target antigen is FOLR1. In some embodiments, the one or more neoplastic cells are derived from an ovarian cancer expressing FOLR1. 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 modulator when administered alone. In some embodiments, the subject is intolerant, unresponsive, or poorly responsive to treatment with a splicing modulator when administered alone.

[0271] In some embodiments, the target antigen is HAVCR1. In some embodiments, the one or more neoplastic cells are derived from renal or esophageal cancer expressing HAVCR1. In some embodiments, the subject is unresponsive 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, unresponsive, or poorly responsive to treatment with a splicing regulator when administered alone.

[0272] In some embodiments, the target antigen is KIT. In some embodiments, the one or more neoplastic cells are derived from a renal cancer that expresses KIT. In some embodiments, the subject is unresponsive or responds poorly 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, unresponsive, or responds poorly to treatment with a splicing regulator when administered alone.

[0273] In some embodiments, the target antigen is MET. In some embodiments, the one or more neoplastic cells are derived from renal or esophageal cancer that expresses MET. In some embodiments, the subject is unresponsive or responds poorly 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, unresponsive, or responds poorly to treatment with a splicing regulator when administered alone.

[0274] In some embodiments, the target antigen is MUC16. In some embodiments, the one or more neoplastic cells are derived from an ovarian cancer, a cervical cancer, or a breast cancer that expresses MUC16. In some embodiments, the subject is unresponsive or responds poorly to treatment with (a) an anti-MUC16 antibody when administered alone and / or (b) a splicing modulator when administered alone. In some embodiments, the subject is intolerant, unresponsive, or responds poorly to treatment with a splicing modulator when administered alone.

[0275] In some embodiments, the target antigen is SLC39A6. In some embodiments, the one or more neoplastic cells are derived from a breast cancer or prostate cancer that expresses SLC39A6. In some embodiments, the subject is unresponsive or responds poorly to treatment with (a) an anti-SLC39A6 antibody when administered alone and / or (b) a splicing modulator when administered alone. In some embodiments, the subject is intolerant, unresponsive, or responds poorly to treatment with a splicing modulator when administered alone.

[0276] In some embodiments, the target antigen is SLC44A4. In some embodiments, the one or more neoplastic cells are derived from a prostate cancer expressing SLC44A4. In some embodiments, the subject is unresponsive or responds poorly to treatment with (a) an anti-SLC44A4 antibody when administered alone and / or (b) a splicing modulator when administered alone. In some embodiments, the subject is intolerant, unresponsive, or responds poorly to treatment with a splicing modulator when administered alone.

[0277] In some embodiments, the target antigen is STEAP1. In some embodiments, the one or more neoplastic cells are derived from a prostate cancer expressing STEAP1. 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 modulator when administered alone. In some embodiments, the subject is intolerant, unresponsive, or poorly responsive to treatment with a splicing modulator when administered alone.

[0278] In certain other aspects, the 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 regimen of any of the described ADCs or compositions.

[0279] In some embodiments, treatment with the 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.

[0280] In some embodiments, the target antigen is HER2. In some embodiments, the one or more neoplastic cells are derived from 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 that expresses HER2. In some embodiments, 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.

[0281] In some embodiments, the target antigen is CD 138. In some embodiments, the one or more neoplastic cells are derived from a multiple myeloma that expresses CD 138. In some embodiments, the tumor is resistant or refractory to treatment with (a) an anti-CD 138 antibody when administered alone and / or (b) a splicing regulator when administered alone.

[0282] In some embodiments, the target antigen is EPHA2. In some embodiments, the one or more neoplastic cells are derived from a breast cancer, prostate cancer, ovarian cancer, lung cancer, melanoma, colon cancer, or esophageal cancer that expresses EPHA2. In some embodiments, 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.

[0283] In some embodiments, the target antigen is MSLN. In some embodiments, the one or more neoplastic cells are derived from ovarian cancer, cervical cancer, pancreatic cancer, or lung cancer (e.g., lung adenocarcinoma) that expresses MSLN. 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.

[0284] In some embodiments, the target antigen is FOLH1. In some embodiments, the one or more neoplastic cells are derived from a prostate cancer expressing FOLH1. 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.

[0285] In some embodiments, the target antigen is CDH6. In some embodiments, the one or more neoplastic cells are derived from a renal cancer that expresses CDH6. 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.

[0286] In some embodiments, the target antigen is CEACAM5. In some embodiments, the one or more neoplastic cells are derived from a colorectal cancer expressing CEACAM5. 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.

[0287] In some embodiments, the target antigen is CFC1B. In some embodiments, the one or more neoplastic cells are derived from a pancreatic cancer that expresses CFC1B. 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.

[0288] In some embodiments, the target antigen is ENPP3. In some embodiments, the one or more neoplastic cells are derived from a renal cancer that expresses ENPP3. 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.

[0289] In some embodiments, the target antigen is FOLR1. In some embodiments, the one or more neoplastic cells are derived from an ovarian cancer that expresses FOLR1. 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.

[0290] In some embodiments, the target antigen is HAVCR1. In some embodiments, the one or more neoplastic cells are derived from a renal or esophageal cancer that expresses HAVCR1. 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.

[0291] In some embodiments, the target antigen is KIT. In some embodiments, the one or more neoplastic cells are derived from a renal cancer that expresses KIT. 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.

[0292] In some embodiments, the target antigen is MET. In some embodiments, the one or more neoplastic cells are derived from a renal or esophageal cancer that expresses MET. 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.

[0293] In some embodiments, the target antigen is MUC16. In some embodiments, the one or more neoplastic cells are derived from an ovarian, cervical, or breast cancer that expresses MUC16. 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.

[0294] In some embodiments, the target antigen is SLC39A6. In some embodiments, the one or more neoplastic cells are derived from a breast cancer or prostate cancer that expresses SLC39A6. 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.

[0295] In some embodiments, the target antigen is SLC44A4. In some embodiments, the one or more neoplastic cells are derived from a prostate cancer that expresses SLC44A4. 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.

[0296] In some embodiments, the target antigen is STEAP1. In some embodiments, the one or more neoplastic cells are derived from a prostate cancer expressing STEAP1. 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.

[0297] In still other aspects, the present disclosure provides a method for determining whether a subject suffering from or suspected of having a neoplastic disorder will respond to treatment with any of the ADCs or compositions 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, a blood fraction, or cells obtained from the blood or blood fraction. In some embodiments, the subject has one or more neoplastic cells expressing a target antigen. In some embodiments, the target antigen is HER2. In some embodiments, the one or more neoplastic cells are derived from 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 expressing HER2. In some embodiments, the target antigen is CD138. In some embodiments, the one or more neoplastic cells are derived from multiple myeloma expressing CD138. In some embodiments, the target antigen is EPHA2. In some embodiments, the one or more neoplastic cells are derived from breast cancer, prostate cancer, ovarian cancer, lung cancer, melanoma, colon cancer, or esophageal cancer that expresses EPHA2. In some embodiments, the target antigen is MSLN. In some embodiments, the one or more neoplastic cells are derived from ovarian cancer, cervical cancer, pancreatic cancer, or lung cancer (e.g., lung adenocarcinoma) that expresses MSLN. In some embodiments, the target antigen is FOLH1. In some embodiments, the one or more neoplastic cells are derived from prostate cancer that expresses FOLH1. In some embodiments, the target antigen is CDH6. In some embodiments, the one or more neoplastic cells are derived from renal cancer that expresses CDH6. In some embodiments, the target antigen is CEACAM5. In some embodiments, the one or more neoplastic cells are derived from colorectal cancer that expresses CEACAM5. In some embodiments, the target antigen is CFC1B. In some embodiments, the one or more neoplastic cells are derived from pancreatic cancer that expresses CFC1B. In some embodiments, the target antigen is ENPP3. In some embodiments, the one or more neoplastic cells are derived from renal cancer that expresses ENPP3. In some embodiments, the target antigen is FOLR1. In some embodiments, the one or more neoplastic cells are derived from ovarian cancer expressing FOLR1. In some embodiments, the target antigen is HAVCR1. In some embodiments, the one or more neoplastic cells are derived from renal or esophageal cancer expressing HAVCR1. In some embodiments, the target antigen is KIT. In some embodiments, the one or more neoplastic cells are derived from renal or esophageal cancer expressing KIT. In some embodiments, the target antigen is MET. In some embodiments, the one or more neoplastic cells are derived from renal or esophageal cancer expressing MET. In some embodiments, the target antigen is MUC16.In some embodiments, the one or more neoplastic cells are derived from ovarian, cervical, or breast cancer expressing MUC16. In some embodiments, the target antigen is SLC39A6. In some embodiments, the one or more neoplastic cells are derived from breast or prostate cancer expressing SLC39A6. In some embodiments, the target antigen is SLC44A4. In some embodiments, the one or more neoplastic cells are derived from prostate cancer expressing SLC44A4. In some embodiments, the target antigen is STEAP1. In some embodiments, the one or more neoplastic cells are derived from prostate cancer expressing STEAP1.

[0298] In various embodiments, the present invention further provides pharmaceutical compositions comprising an ADC and a pharmaceutically acceptable diluent, carrier, and / or excipient. Methods of making the ADC complexes and compositions are also disclosed.

[0299] This application relates to the following items:

[0300] Item 1. An antibody-drug conjugate of formula (I),

[0301] Ab-(LD) p (I)

[0302] in

[0303] Ab is an antibody or antigen-binding fragment that targets neoplastic cells;

[0304] D is a splicing regulator;

[0305] L is a linker that covalently links Ab to D; and

[0306] p is an integer from 1 to 15.

[0307] Item 2. The antibody-drug conjugate of Item 1, wherein the antibody or antigen-binding fragment targets neoplastic cells derived from a hematological malignancy or a solid tumor.

[0308] Item 3. The antibody-drug conjugate of Item 1 or Item 2, wherein the antibody or antigen-binding fragment targets neoplastic cells derived from a hematological malignancy.

[0309] Item 4. The antibody-drug conjugate of Item 3, wherein the hematological malignancy is selected from B-cell malignancies, leukemias, lymphomas, and myelomas.

[0310] Item 5. The antibody-drug conjugate of Item 3 or Item 4, wherein the hematological malignancy is selected from acute myeloid leukemia and multiple myeloma.

[0311] Item 6. The antibody-drug conjugate of Item 1 or Item 2, wherein the antibody or antigen-binding fragment targets neoplastic cells derived from a solid tumor.

[0312] Item 7. The antibody-drug conjugate of Item 6, wherein the solid tumor is selected from breast cancer, gastric cancer, prostate cancer, ovarian cancer, lung cancer, uterine cancer, salivary duct carcinoma, melanoma, colon cancer, cervical cancer, pancreatic cancer, renal cancer, colorectal cancer and esophageal cancer.

[0313] Item 8. The antibody-drug conjugate of any one of Items 1 to 7, wherein the antibody or antigen-binding fragment targets cells expressing HER2.

[0314] Item 9. The antibody-drug conjugate of Item 8, wherein the antibody or antigen-binding fragment is an anti-HER2 antibody or antigen-binding fragment.

[0315] Item 10. An antibody-drug conjugate as described in Item 8 or Item 9, wherein the antibody or antigen-binding fragment comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) comprising 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) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2) and SEQ ID NO: 6 (LCDR3).

[0316] Item 11. The antibody-drug conjugate of any one of Items 8 to 10, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 19 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 20.

[0317] Item 12. The antibody-drug conjugate of any one of Items 8 to 11, wherein the antibody or antigen-binding fragment comprises a human IgG1 heavy chain constant region.

[0318] Item 13. The antibody-drug conjugate of any one of Items 8 to 12, wherein the antibody or antigen-binding fragment comprises a human Ig kappa light chain constant region.

[0319] Item 14. The antibody-drug conjugate of any one of Items 1 to 7, wherein the antibody or antigen-binding fragment targets cells expressing CD138.

[0320] Item 15. The antibody-drug conjugate of Item 14, wherein the antibody or antigen-binding fragment is an anti-CD138 antibody or antigen-binding fragment.

[0321] Item 16. An antibody-drug conjugate as described in Item 14 or Item 15, wherein the antibody or antigen-binding fragment comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) comprising the amino acid sequences of 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) comprising the amino acid sequences of SEQ ID NO: 10 (LCDR1), SEQ ID NO: 11 (LCDR2) and SEQ ID NO: 12 (LCDR3).

[0322] Item 17. The antibody-drug conjugate of any one of Items 14 to 16, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 21 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 22.

[0323] Item 18. The antibody-drug conjugate of any one of Items 14 to 17, wherein the antibody or antigen-binding fragment comprises a human IgG2a heavy chain constant region.

[0324] Item 19. The antibody-drug conjugate of any one of Items 14 to 18, wherein the antibody or antigen-binding fragment comprises a human Ig kappa light chain constant region.

[0325] Item 20. The antibody-drug conjugate of any one of Items 1 to 7, wherein the antibody or antigen-binding fragment targets cells expressing EPHA2.

[0326] Item 21. The antibody-drug conjugate of Item 20, wherein the antibody or antigen-binding fragment is an anti-EPHA2 antibody or antigen-binding fragment.

[0327] Item 22. An antibody-drug conjugate as described in Item 20 or Item 21, wherein the antibody or antigen-binding fragment comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) comprising the amino acid sequences of 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) comprising the amino acid sequences of SEQ ID NO: 16 (LCDR1), SEQ ID NO: 17 (LCDR2) and SEQ ID NO: 18 (LCDR3).

[0328] Item 23. An antibody-drug conjugate as described in any one of Items 20 to 22, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 23 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 24.

[0329] Item 24. The antibody-drug conjugate of any one of Items 20 to 23, wherein the antibody or antigen-binding fragment comprises a human IgG1 heavy chain constant region.

[0330] Item 25. The antibody-drug conjugate of any one of Items 20 to 24, wherein the antibody or antigen-binding fragment comprises a human Ig kappa light chain constant region.

[0331] Item 26. The antibody-drug conjugate of any one of Items 1 to 25, wherein the linker is a cleavable linker.

[0332] Item 27. The antibody-drug conjugate of Item 26, wherein the linker comprises a cleavable peptide portion.

[0333] Item 28. The antibody-drug conjugate of Item 27, wherein the cleavable peptide portion is cleavable by an enzyme.

[0334] Item 29. The antibody-drug conjugate of any one of Items 26 to 28, wherein the cleavable peptide portion or linker comprises amino acid units.

[0335] Item 30. The antibody-drug conjugate of Item 29, wherein the amino acid unit comprises valine-citrulline (Val-Cit).

[0336] Item 31. The antibody-drug conjugate of Item 29, wherein the amino acid unit comprises valine-alanine (Val-Ala).

[0337] Item 32. The antibody-drug conjugate of Item 26, wherein the linker comprises a cleavable glucuronide moiety.

[0338] Item 33. The antibody-drug conjugate of Item 32, wherein the cleavable glucuronide portion is cleavable by an enzyme.

[0339] Item 34. The antibody-drug conjugate of Item 32 or Item 33, wherein the cleavable glucuronide moiety is cleavable by glucuronidase.

[0340] Item 35. The antibody-drug conjugate of any one of Items 32 to 34, wherein the cleavable glucuronide moiety is cleavable by β-glucuronidase.

[0341] Item 36. The antibody-drug conjugate of any one of Items 1 to 35, wherein the linker comprises at least one spacer unit.

[0342] Item 37. The antibody-drug conjugate of Item 36, wherein the spacer unit or linker comprises a polyethylene glycol (PEG) portion.

[0343] Item 38. The antibody-drug conjugate of Item 37, wherein the PEG moiety comprises -(PEG) m - and m is an integer from 1 to 10.

[0344] Item 39. The antibody-drug conjugate of Item 38, wherein m is 2.

[0345] Item 40. The antibody-drug conjugate of Item 36, wherein the spacer unit or linker comprises an alkyl portion.

[0346] Item 41. The antibody-drug conjugate of Item 40, wherein the alkyl moiety comprises -(CH2) n - and n is an integer from 1 to 10.

[0347] Item 42. The antibody-drug conjugate of Item 41, wherein n is 2.

[0348] Item 43. The antibody-drug conjugate of Item 41, wherein n is 5.

[0349] Item 44. The antibody-drug conjugate of Item 41, wherein n is 6.

[0350] Item 45. The antibody-drug conjugate of any one of Items 36 to 44, wherein the spacer unit is linked to the antibody or antigen-binding fragment via a maleimide (Mal) moiety ("Mal-Spacer unit").

[0351] Item 46. The antibody-drug conjugate of Item 45, wherein the Mal-Spacer unit is reactive with a cysteine ​​residue on the antibody or antigen-binding fragment.

[0352] Item 47. The antibody-drug conjugate of Item 45 or Item 46, wherein the Mal-Spacer unit is attached to the antibody or antigen-binding fragment via a cysteine ​​residue on the antibody or antigen-binding fragment.

[0353] Item 48. The antibody-drug conjugate of any one of Items 45 to 47, wherein the linker comprises the Mal-Spacer unit and a cleavable peptide portion.

[0354] Item 49. The antibody-drug conjugate of Item 48, wherein the cleavable peptide portion comprises amino acid units.

[0355] Item 50. The antibody-drug conjugate of Item 48 or Item 49, wherein the cleavable peptide portion or amino acid unit comprises Val-Cit.

[0356] Item 51. The antibody-drug conjugate of Item 48 or Item 49, wherein the cleavable peptide portion or amino acid unit comprises Val-Ala.

[0357] Item 52. The antibody-drug conjugate of any one of Items 45 to 51, wherein the Mal-Spacer unit comprises an alkyl moiety.

[0358] Item 53. The antibody-drug conjugate of any one of Items 45 to 51, wherein the Mal-Spacer unit comprises a PEG moiety.

[0359] Item 54. The antibody-drug conjugate of any one of Items 45 to 52, wherein the Mal-Spacer unit comprises a maleimidocaproyl group (MC).

[0360] Item 55. The antibody-drug conjugate of any one of Items 45 to 54, wherein the Mal-Spacer unit connects the antibody or antigen-binding fragment to the cleavable moiety in the linker.

[0361] Item 56. An antibody-drug conjugate as described in Item 55, wherein the cleavable portion in the linker comprises a cleavable peptide portion.

[0362] Item 57. The antibody-drug conjugate of Item 56, wherein the cleavable peptide portion comprises amino acid units.

[0363] Item 58. The antibody-drug conjugate of Item 56 or Item 57, wherein the cleavable peptide portion or amino acid unit comprises Val-Cit, Val-Ala, Glu-Val-Cit or Ala-Ala-Asn.

[0364] Item 59. The antibody-drug conjugate of any one of Items 55 to 58, wherein the linker comprises MC-Val-Cit.

[0365] Item 60. The antibody-drug conjugate of any one of Items 55 to 58, wherein the linker comprises MC-Val-Ala.

[0366] Item 61. The antibody-drug conjugate of any one of Items 55 to 60, wherein the Mal-Spacer unit comprises an alkyl moiety.

[0367] Item 62. The antibody-drug conjugate of any one of Items 55 to 60, wherein the Mal-Spacer unit comprises a PEG moiety.

[0368] Item 63. The antibody-drug conjugate of any one of Items 55 to 61, wherein the Mal-Spacer unit comprises a maleimidocaproyl group (MC).

[0369] Item 64. An antibody-drug conjugate as described in any of Items 36 to 63, wherein the cleavable portion in the linker is directly attached to the splicing regulator, or wherein the spacer unit connects the cleavable portion in the linker to the splicing regulator.

[0370] Item 65. The antibody-drug conjugate of Item 64, wherein cleavage of the conjugate releases the splicing regulator from the antibody or antigen-binding fragment and the linker.

[0371] Item 66. The antibody-drug conjugate of Item 64 or Item 65, wherein the spacer unit connecting the cleavable portion of the linker to the splicing regulator is self-ablative.

[0372] Item 67. The antibody-drug conjugate of any one of Items 64 to 66, wherein the spacer unit connecting the cleavable moiety in the linker to the splicing regulator comprises a p-aminobenzyloxycarbonyl group (pABC).

[0373] Item 68. The antibody-drug conjugate of Item 67, wherein the pABC connects the cleavable portion in the linker to the splicing regulator.

[0374] Item 69. The antibody-drug conjugate of Item 67 or Item 68, wherein the cleavable portion in the linker comprises a cleavable peptide portion.

[0375] Item 70. The antibody-drug conjugate of Item 69, wherein the cleavable peptide portion comprises amino acid units.

[0376] Item 71. The antibody-drug conjugate of Item 69 or Item 70, wherein the cleavable peptide portion or amino acid unit comprises Val-Cit, Val-Ala, Glu-Val-Cit or Ala-Ala-Asn.

[0377] Item 72. The antibody-drug conjugate of any one of Items 67 to 71, wherein the linker comprises Val-Cit-pABC.

[0378] Item 73. The antibody-drug conjugate of any one of Items 67 to 71, wherein the linker comprises Val-Ala-pABC.

[0379] Item 74. The antibody-drug conjugate of any one of Items 64 to 66, wherein the spacer unit connecting the cleavable moiety in the linker to the splicing regulator comprises a p-aminobenzyl group (pAB).

[0380] Item 75. The antibody-drug conjugate of Item 74, wherein the pAB connects the cleavable portion in the linker to the splicing regulator.

[0381] Item 76. The antibody-drug conjugate of Item 74 or Item 75, wherein the cleavable portion in the linker comprises a cleavable peptide portion.

[0382] Item 77. The antibody-drug conjugate of Item 76, wherein the cleavable peptide portion comprises amino acid units.

[0383] Item 78. The antibody-drug conjugate of Item 76 or Item 77, wherein the cleavable peptide portion or amino acid unit comprises Val-Cit, Val-Ala, Glu-Val-Cit or Ala-Ala-Asn.

[0384] Item 79. The antibody-drug conjugate of any one of Items 74 to 78, wherein the linker comprises Val-Cit-pAB.

[0385] Item 80. The antibody-drug conjugate of any one of Items 74 to 78, wherein the linker comprises Val-Ala-pAB.

[0386] Item 81. The antibody-drug conjugate of any one of Items 1 to 25, wherein the linker is a non-cleavable linker.

[0387] Item 82. The antibody-drug conjugate of Item 81, wherein the linker comprises at least one spacer unit.

[0388] Item 83. The antibody-drug conjugate of Item 81 or Item 82, wherein the spacer unit or linker comprises a polyethylene glycol (PEG) moiety.

[0389] Item 84. The antibody-drug conjugate of Item 83, wherein the PEG moiety comprises -(PEG) m - and m is an integer from 1 to 10.

[0390] Item 85. The antibody-drug conjugate of Item 84, wherein m is 2.

[0391] Item 86. The antibody-drug conjugate of Item 81 or Item 82, wherein the spacer unit or linker comprises an alkyl portion.

[0392] Item 87. The antibody-drug conjugate of Item 86, wherein the alkyl moiety comprises -(CH2) n - and n is an integer from 1 to 10.

[0393] Item 88. The antibody-drug conjugate of Item 87, wherein n is 2.

[0394] Item 89. The antibody-drug conjugate of Item 87, wherein n is 5.

[0395] Item 90. The antibody-drug conjugate of Item 87, wherein n is 6.

[0396] Item 91. The antibody-drug conjugate of any one of Items 81 to 90, wherein the spacer unit is linked to the antibody or antigen-binding fragment via a maleimide (Mal) moiety ("Mal-Spacer unit").

[0397] Item 92. The antibody-drug conjugate of Item 91, wherein the Mal-Spacer unit is reactive with a cysteine ​​residue on the antibody or antigen-binding fragment.

[0398] Item 93. The antibody-drug conjugate of Item 91 or Item 92, wherein the Mal-Spacer unit is attached to the antibody or antigen-binding fragment via a cysteine ​​residue on the antibody or antigen-binding fragment.

[0399] Item 94. The antibody-drug conjugate of any one of Items 91 to 93, wherein the Mal-Spacer unit comprises an alkyl portion.

[0400] Item 95. The antibody-drug conjugate of any one of Items 91 to 93, wherein the Mal-Spacer unit comprises a PEG moiety.

[0401] Item 96. The antibody-drug conjugate of any one of Items 91 to 95, wherein the linker or Mal-Spacer unit comprises a maleimidocaproyl group (MC).

[0402] Item 97. The antibody-drug conjugate of Item 96, wherein the linker or Mal-spacer unit comprises maleimidocaproyl (MC) and at least one additional spacer unit.

[0403] Item 98. The antibody-drug conjugate of any one of Items 91 to 95, wherein the linker or Mal-spacer unit comprises MC-(PEG)2.

[0404] Item 99. The antibody-drug conjugate of Item 98, wherein the linker or Mal-spacer unit comprises MC-(PEG)2 and at least one additional spacer unit.

[0405] Item 100. The antibody-drug conjugate of any one of Items 91 to 95, wherein the linker or Mal-spacer unit comprises Mal-Hex.

[0406] Item 101. The antibody-drug conjugate of Item 100, wherein the linker or Mal-spacer unit comprises MC-Hex and at least one additional spacer unit.

[0407] Item 102. The antibody-drug conjugate of any one of Items 91 to 95, wherein the linker or Mal-spacer unit comprises Mal-Et.

[0408] Item 103. The antibody-drug conjugate of Item 102, wherein the linker or Mal-spacer unit comprises Mal-Et and at least one additional spacer unit.

[0409] Item 104. The antibody-drug conjugate of any one of Items 91 to 95, wherein the linker or Mal-Spacer unit comprises Mal-Et-O-Et.

[0410] Item 105. The antibody-drug conjugate of Item 104, wherein the linker or Mal-spacer unit comprises Mal-Et-O-Et and at least one additional spacer unit.

[0411] Item 106. The antibody-drug conjugate of any one of Items 91 to 105, wherein the Mal-Spacer unit links the antibody or antigen-binding fragment to the splicing regulator.

[0412] Item 107. The antibody-drug conjugate of any one of Items 1 to 106, wherein the splicing regulator comprises a splicing regulator having Formula (II):

[0413] or a pharmaceutically acceptable salt thereof, wherein:

[0414] R 1 is selected from the group consisting of absence, hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group, a -OC(=O)-(C1-C6 alkyl) group, and -CD3;

[0415] R 3 is selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group and a -OC(=O)-(C1-C6 alkyl) group; and

[0416] R 4 、R 5 and R 8are each independently selected from hydrogen, a hydroxyl group, an —O—(C 1 -C 6 alkyl) group, a —OC(═O)—(C 1 -C 6 alkyl) group, and a C 1 -C 6 alkyl group;

[0417] R 6 and R 7 are each independently selected from hydrogen, -OR 17 、-OC(=O)-R 17 、-OC(=O)-NR 15 R 16 , C1-C6 alkyl groups and -NR 15 R 16 ;

[0418] R 15 and R 16 are each independently selected from hydrogen, R 17 、-C(=O)-R 17 and -C(=O)-OR 17 ;

[0419] R 17 is selected from hydrogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a benzyl group and a C3-C8 heterocyclyl group; and

[0420] Z is selected from

[0421] where R 1 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 15 、R 16 and R 17 Each is independently substituted by 0 to 3 groups independently selected from the following: halogen, hydroxyl group, C1-C6 alkyl group, -O-(C1-C6 alkyl) group, -NR 15 R 16 , a C3-C8 cycloalkyl group, a C1-C6 alkylhydroxyl group, a C1-C6 alkylalkoxy group, a benzyl group and a C3-C8 heterocyclyl group,

[0422] where R 6 and R 7 At least one of them is hydrogen.

[0423] Item 108. The antibody-drug conjugate of Item 107, wherein the linker is covalently attached to the splicing regulator ("LD"), and LD has the structure of Formula (II-A):

[0424] or a pharmaceutically acceptable salt thereof,

[0425] Where Z' is selected from and

[0426] wherein all other variables are as defined with respect to formula (II).

[0427] Item 109. The antibody-drug conjugate of any one of Items 1 to 106, wherein the splicing regulator is a splicing regulator of Formula (IV):

[0428] or a pharmaceutically acceptable salt thereof, wherein:

[0429] R 1 is selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group, a -OC(=O)-(C1-C6 alkyl) group and -CD3;

[0430] R 3 is selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group and a -OC(=O)-(C1-C6 alkyl) group; and

[0431] R 4 、R 5 and R 8 are each independently selected from hydrogen, a hydroxyl group, an —O—(C 1 -C 6 alkyl) group, a —OC(═O)—(C 1 -C 6 alkyl) group, and a C 1 -C 6 alkyl group;

[0432] R 6 and R 7 are each independently selected from hydrogen, -OR 17 、-OC(=O)-R 17 、-OC(=O)-NR 15 R 16 , C1-C6 alkyl groups and -NR 15 R 16 ;

[0433] R 15 and R 16 are each independently selected from hydrogen, R 17 、-C(=O)-R 17and -C(=O)-OR 17 ;and

[0434] R 17 is selected from hydrogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a benzyl group and a C3-C8 heterocyclyl group;

[0435] where R 1 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 15 、R 16 and R 17 Each is independently substituted by 0 to 3 groups independently selected from the following: halogen, hydroxyl group, C1-C6 alkyl group, -O-(C1-C6 alkyl) group, -NR 15 R 16 , a C3-C8 cycloalkyl group, a C1-C6 alkylhydroxyl group, a C1-C6 alkylalkoxy group, a benzyl group and a C3-C8 heterocyclyl group,

[0436] where R 6 and R 7 At least one of them is hydrogen.

[0437] Item 110. The antibody-drug conjugate of Item 109, wherein the linker is covalently attached to the splicing regulator ("LD"), and LD has the structure of Formula (IV-A):

[0438] or a pharmaceutically acceptable salt thereof.

[0439] Item 111. The antibody-drug conjugate of any one of Items 1 to 106, wherein the splicing regulator is a splicing regulator having Formula (VI):

[0440] or a pharmaceutically acceptable salt thereof, wherein:

[0441] R 1 and R 9 Each is independently selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group, a -OC(=O)-(C1-C6 alkyl) group and -CD3;

[0442] R 3is selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group and a -OC(=O)-(C1-C6 alkyl) group;

[0443] R 4 、R 5 and R 8 are each independently selected from hydrogen, a hydroxyl group, an —O—(C 1 -C 6 alkyl) group, a —OC(═O)—(C 1 -C 6 alkyl) group, and a C 1 -C 6 alkyl group;

[0444] R 6 and R 7 are each independently selected from hydrogen, -OR 17 、-OC(=O)-R 17 、-OC(=O)-NR 15 R 16 , C1-C6 alkyl group, -NR 15 R 16 and joints;

[0445] R 10 is selected from hydrogen, a C1-C6 alkyl group, a -C(=O)-(C1-C6 alkyl) group and -CD3;

[0446] R 15 and R 16 are each independently selected from hydrogen, R 17 、-C(=O)-R 17 and -C(=O)-OR 17 ;

[0447] R 17 is selected from hydrogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a benzyl group and a C3-C8 heterocyclyl group; and

[0448] a is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0449] where R 1 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 15 、R 16 and R 17Each is independently substituted by 0 to 3 groups independently selected from the following: halogen, hydroxyl group, C1-C6 alkyl group, -O-(C1-C6 alkyl) group, -NR 15 R 16 , a C3-C8 cycloalkyl group, a C1-C6 alkylhydroxyl group, a C1-C6 alkylalkoxy group, a benzyl group and a C3-C8 heterocyclyl group;

[0450] where R 6 and R 7 At least one of is hydrogen; and

[0451] where R 1 and R 9 Cannot exist at the same time.

[0452] Item 112. The antibody-drug conjugate of Item 111, wherein the linker is covalently attached to the splicing regulator ("LD"), and LD has the structure of Formula (VI-A):

[0453] or a pharmaceutically acceptable salt thereof.

[0454] Item 113. The antibody-drug conjugate of any one of Items 1 to 106, wherein the splicing regulator is a splicing regulator having Formula (VIII):

[0455] or a pharmaceutically acceptable salt thereof, wherein:

[0456] R 1 is selected from the group consisting of absence, hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group, a -OC(=O)-(C1-C6 alkyl) group, and -CD3;

[0457] R 3 is selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group and a -OC(=O)-(C1-C6 alkyl) group;

[0458] R 4 is selected from hydrogen, a hydroxyl group, an —O—(C 1 -C 6 alkyl) group, a —OC(═O)—(C 1 -C 6 alkyl) group, and a C 1 -C 6 alkyl group; and

[0459] R 10selected from 3 to 10 membered carbocyclic rings and 3 to 10 membered heterocyclic rings, each of which is surrounded by 0 to 3 R a Substitute, where each R a independently selected from halogen, C1-C6 alkyl group, -O-(C1-C6)alkyl group, C1-C6 alkylalkoxy group, C1-C6 alkylhydroxyl group, -S(=O) w -(4- to 7-membered heterocyclic ring), 4- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring;

[0460] R 15 and R 16 are each independently selected from hydrogen, R 17 、-C(=O)-R 17 and -C(=O)-OR 17 ;and

[0461] R 17 is selected from hydrogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a benzyl group and a C3-C8 heterocyclyl group;

[0462] where R 1 、R 3 、R 4 、R 10 、R 15 、R 16 and R 17 Each is independently substituted by 0 to 3 groups independently selected from the following: halogen, hydroxyl group, C1-C6 alkyl group, -O-(C1-C6 alkyl) group, -NR 15 R 16 , a C3-C8 cycloalkyl group, a C1-C6 alkylhydroxy group, a C1-C6 alkylalkoxy group, a benzyl group, and a C3-C8 heterocyclyl group; and

[0463] Each R a is independently substituted with 0 to 3 groups independently selected from the group consisting of halogen, hydroxyl, -NR 15 R 16 , C1-C6 alkyl group, -(C=O)-(C1-C6 alkyl) group, -(C=O)-(C1-C6 alkyl)-(C3-C 10 heterocyclyl) group, -S(=O) w -(C3-C8 heterocyclyl group) and C1-C6 alkylcarboxylic acid group, each of which is substituted by 0, 1 or 2 groups independently selected from the group consisting of halogen, hydroxyl group, -NR 15 R 16 and a C1-C3 alkyl group; and

[0464] w is 0, 1, or 2.

[0465] Item 114. The antibody-drug conjugate of Item 113, wherein the linker is covalently attached to the splicing regulator ("LD"), and LD has the structure of Formula (VIII-A):

[0466] or a pharmaceutically acceptable salt thereof.

[0467] Item 115. The antibody-drug conjugate of any one of Items 1 to 106, wherein the splicing regulator comprises a regulator of the SF3b complex.

[0468] Item 116. The antibody-drug conjugate of Item 115, wherein the splicing regulator comprises pradienolide or a pradienolide derivative.

[0469] Item 117. The antibody-drug conjugate of Item 115 or Item 116, wherein the splicing regulator comprises pradienolide D or a pradienolide D derivative.

[0470] Item 118. The antibody-drug conjugate of Item 117, wherein the pradienolide D or derivative comprises D2, D1, D4, D8, D10, D11 (E7107), D20, D21, D22, D12 or D25.

[0471] Item 119. The antibody-drug conjugate of Item 117 or Item 118, wherein the pradienolide D or derivative comprises D2.

[0472] Item 120. The antibody-drug conjugate of Item 117 or Item 118, wherein the pradienolide D or derivative comprises D1.

[0473] Item 121. The antibody-drug conjugate of Item 117 or Item 118, wherein the pradienolide D or derivative is a zwitterionic pradienolide D or derivative.

[0474] Item 122. The antibody-drug conjugate of Item 121, wherein the zwitterionic pradienolide D or derivative comprises D22 or D25.

[0475] Item 123. The antibody-drug conjugate of Item 115 or Item 116, wherein the splicing regulator comprises pradienolide B or a pradienolide B derivative.

[0476] Item 124. The antibody-drug conjugate of Item 123, wherein the pradienolide B or derivative comprises D9, D18, D19 or D13.

[0477] Item 125. The antibody-drug conjugate of Item 115 or Item 116, wherein the splicing regulator comprises an aryl pramide diene lactone.

[0478] Item 126. The antibody-drug conjugate of Item 125, wherein the aryl pramide diene lactone comprises D15, D14, D16, D17, D26 or D33.

[0479] Item 127. The antibody-drug conjugate of Item 125 or Item 126, wherein the aryl pramide diene lactone is a zwitterionic aryl pramide diene lactone.

[0480] Item 128. The antibody-drug conjugate of Item 127, wherein the zwitterionic aryl pramide diene lactone comprises D33.

[0481] Item 129. The antibody-drug conjugate of any one of Items 1 to 106, wherein the splicing regulator comprises D2:

[0482]

[0483] Item 130. The antibody-drug conjugate of any one of Items 1 to 106, wherein the splicing regulator comprises D1:

[0484]

[0485] Item 131. The antibody-drug conjugate of any one of Items 1 to 106, wherein the splicing regulator comprises D4, D12, D15, D8, D9, D10, D13, D18, D19, D20, D21, D22, D25 or D33.

[0486] Item 132. The antibody-drug conjugate of any one of Items 1 to 131, wherein p is 1 to 10.

[0487] Item 133. The antibody-drug conjugate of any one of Items 1 to 132, wherein p is 2 to 8.

[0488] Item 134. The antibody-drug conjugate of any one of Items 1 to 133, wherein p is 4 to 8.

[0489] Item 135. The antibody-drug conjugate of any one of Items 1 to 134, wherein p is 4.

[0490] Item 136. The antibody-drug conjugate of any one of Items 1 to 134, wherein p is 8.

[0491] Item 137. An antibody-drug conjugate having formula (I),

[0492] Ab-(LD) p (I)

[0493] in

[0494] Ab is an antibody or antigen-binding fragment that targets neoplastic cells;

[0495] D is D2;

[0496] L is a linker that covalently links Ab to D; and

[0497] p is an integer from 1 to 15.

[0498] Item 138. The antibody-drug conjugate of Item 137, wherein the antibody or antigen-binding fragment targets cells expressing HER2.

[0499] Item 139. The antibody-drug conjugate of Item 138, wherein the antibody or antigen-binding fragment is an anti-HER2 antibody or antigen-binding fragment.

[0500] Item 140. An antibody-drug conjugate as described in Item 138 or Item 139, wherein the antibody or antigen-binding fragment comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) comprising 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) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2) and SEQ ID NO: 6 (LCDR3).

[0501] Item 141. An antibody-drug conjugate as described in any one of Items 138 to 140, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 19 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 20.

[0502] Item 142. The antibody-drug conjugate of any one of Items 138 to 141, wherein the antibody or antigen-binding fragment comprises a human IgG1 heavy chain constant region.

[0503] Item 143. The antibody-drug conjugate of any one of Items 138 to 142, wherein the antibody or antigen-binding fragment comprises a human Igκ light chain constant region.

[0504] Item 144. The antibody-drug conjugate of Item 137, wherein the antibody or antigen-binding fragment targets cells expressing CD138.

[0505] Item 145. The antibody-drug conjugate of Item 144, wherein the antibody or antigen-binding fragment is an anti-CD138 antibody or antigen-binding fragment.

[0506] Item 146. An antibody-drug conjugate as described in Item 144 or Item 145, wherein the antibody or antigen-binding fragment comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) comprising the amino acid sequence of 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) comprising the amino acid sequence of SEQ ID NO: 10 (LCDR1), SEQ ID NO: 11 (LCDR2) and SEQ ID NO: 12 (LCDR3).

[0507] Item 147. An antibody-drug conjugate as described in any one of Items 144 to 146, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 21 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 22.

[0508] Item 148. The antibody-drug conjugate of any one of Items 144 to 147, wherein the antibody or antigen-binding fragment comprises a human IgG2a heavy chain constant region.

[0509] Item 149. The antibody-drug conjugate of any one of Items 144 to 148, wherein the antibody or antigen-binding fragment comprises a human Igκ light chain constant region.

[0510] Item 150. The antibody-drug conjugate of Item 137, wherein the antibody or antigen-binding fragment targets cells expressing EPHA2.

[0511] Item 151. The antibody-drug conjugate of Item 150, wherein the antibody or antigen-binding fragment is an anti-EPHA2 antibody or antigen-binding fragment.

[0512] Item 152. An antibody-drug conjugate as described in Item 150 or Item 151, wherein the antibody or antigen-binding fragment comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) comprising the amino acid sequences of 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) comprising the amino acid sequences of SEQ ID NO: 16 (LCDR1), SEQ ID NO: 17 (LCDR2) and SEQ ID NO: 18 (LCDR3).

[0513] Item 153. An antibody-drug conjugate as described in any one of Items 150 to 152, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 23 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 24.

[0514] Item 154. The antibody-drug conjugate of any one of Items 150 to 153, wherein the antibody or antigen-binding fragment comprises a human IgG1 heavy chain constant region.

[0515] Item 155. The antibody-drug conjugate of any one of Items 150 to 154, wherein the antibody or antigen-binding fragment comprises a human Igκ light chain constant region.

[0516] Item 156. An antibody-drug conjugate having formula (I),

[0517] Ab-(LD) p (I)

[0518] in

[0519] Ab is an antibody or antigen-binding fragment that targets neoplastic cells;

[0520] D is D1;

[0521] L is a linker that covalently links Ab to D; and

[0522] p is an integer from 1 to 15.

[0523] Item 157. The antibody-drug conjugate of Item 156, wherein the antibody or antigen-binding fragment targets cells expressing HER2.

[0524] Item 158. The antibody-drug conjugate of Item 157, wherein the antibody or antigen-binding fragment is an anti-HER2 antibody or antigen-binding fragment.

[0525] Item 159. An antibody-drug conjugate as described in Item 157 or Item 158, wherein the antibody or antigen-binding fragment comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) comprising 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) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2) and SEQ ID NO: 6 (LCDR3).

[0526] Item 160. The antibody-drug conjugate of any one of Items 157 to 159, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 19 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 20.

[0527] Item 161. The antibody-drug conjugate of any one of Items 157 to 160, wherein the antibody or antigen-binding fragment comprises a human IgG1 heavy chain constant region.

[0528] Item 162. The antibody-drug conjugate of any one of Items 157 to 161, wherein the antibody or antigen-binding fragment comprises a human Igκ light chain constant region.

[0529] Item 163. The antibody-drug conjugate of Item 156, wherein the antibody or antigen-binding fragment targets cells expressing CD138.

[0530] Item 164. The antibody-drug conjugate of Item 163, wherein the antibody or antigen-binding fragment is an anti-CD138 antibody or antigen-binding fragment.

[0531] Item 165. An antibody-drug conjugate as described in Item 163 or Item 164, wherein the antibody or antigen-binding fragment comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) comprising the amino acid sequences of 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) comprising the amino acid sequences of SEQ ID NO: 10 (LCDR1), SEQ ID NO: 11 (LCDR2) and SEQ ID NO: 12 (LCDR3).

[0532] Item 166. An antibody-drug conjugate as described in any one of Items 163 to 165, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 21 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 22.

[0533] Item 167. The antibody-drug conjugate of any one of Items 163 to 166, wherein the antibody or antigen-binding fragment comprises a human IgG2a heavy chain constant region.

[0534] Item 168. The antibody-drug conjugate of any one of Items 163 to 167, wherein the antibody or antigen-binding fragment comprises a human Igκ light chain constant region.

[0535] Item 169. The antibody-drug conjugate of Item 156, wherein the antibody or antigen-binding fragment targets cells expressing EPHA2.

[0536] Item 170. The antibody-drug conjugate of Item 169, wherein the antibody or antigen-binding fragment is an anti-EPHA2 antibody or antigen-binding fragment.

[0537] Item 171. An antibody-drug conjugate as described in Item 169 or Item 170, wherein the antibody or antigen-binding fragment comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) comprising the amino acid sequence of 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) comprising the amino acid sequence of SEQ ID NO: 16 (LCDR1), SEQ ID NO: 17 (LCDR2) and SEQ ID NO: 18 (LCDR3).

[0538] Item 172. An antibody-drug conjugate as described in any one of Items 169 to 171, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 23 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 24.

[0539] Item 173. The antibody-drug conjugate of any one of Items 169 to 172, wherein the antibody or antigen-binding fragment comprises a human IgG1 heavy chain constant region.

[0540] Item 174. The antibody-drug conjugate of any one of Items 169 to 173, wherein the antibody or antigen-binding fragment comprises a human Igκ light chain constant region.

[0541] Item 175. An antibody-drug conjugate having formula (I),

[0542] Ab-(LD) p (I)

[0543] in

[0544] Ab is an anti-HER2 antibody or antigen-binding fragment comprising three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) comprising 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) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3);

[0545] D is D2, D1, D4, D12 or D15;

[0546] L is a linker that covalently links Ab to D; and

[0547] p is an integer from 1 to 15.

[0548] Item 176. An antibody-drug conjugate as described in Item 175, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 19 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 20.

[0549] Item 177. An antibody-drug conjugate having formula (I),

[0550] Ab-(LD) p (I)

[0551] in

[0552] Ab is an anti-CD138 antibody or antigen-binding fragment comprising three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of 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) comprising the amino acid sequences of SEQ ID NO: 10 (LCDR1), SEQ ID NO: 11 (LCDR2), and SEQ ID NO: 12 (LCDR3);

[0553] D is D2, D1, D4, D12 or D15;

[0554] L is a linker that covalently links Ab to D; and

[0555] p is an integer from 1 to 15.

[0556] Item 178. An antibody-drug conjugate as described in Item 177, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 21 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 22.

[0557] Item 179. An antibody-drug conjugate having formula (I),

[0558] Ab-(LD) p (I)

[0559] in

[0560] Ab is an anti-EPHA2 antibody or antigen-binding fragment comprising three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of 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) comprising the amino acid sequences of SEQ ID NO: 16 (LCDR1), SEQ ID NO: 17 (LCDR2), and SEQ ID NO: 18 (LCDR3);

[0561] D is D2, D1, D4, D12 or D15;

[0562] L is a linker that covalently links Ab to D; and

[0563] p is an integer from 1 to 15.

[0564] Item 180. An antibody-drug conjugate as described in Item 179, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 23 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 24.

[0565] Item 181. The antibody-drug conjugate of any one of Items 156 to 180, wherein the linker is a cleavable linker.

[0566] Item 182. The antibody-drug conjugate of Item 181, wherein the cleavable linker comprises MC-Val-Cit-pABC.

[0567] Item 183. The antibody-drug conjugate of Item 181, wherein the cleavable linker comprises MC-Val-Ala-pABC.

[0568] Item 184. The antibody-drug conjugate of Item 181, wherein the cleavable linker comprises MC-Val-Ala-pAB.

[0569] Item 185. The antibody-drug conjugate of any one of Items 156 to 180, wherein the linker is a non-cleavable linker.

[0570] Item 186. The antibody-drug conjugate of Item 185, wherein the non-cleavable linker comprises Mal-Hex.

[0571] Item 187. The antibody-drug conjugate of Item 185, wherein the non-cleavable linker comprises Mal-Et.

[0572] Item 188. The antibody-drug conjugate of Item 185, wherein the non-cleavable linker comprises Mal-Et-O-Et.

[0573] Item 189. The antibody-drug conjugate of any one of Items 156 to 188, wherein p is 1 to 10.

[0574] Item 190. The antibody-drug conjugate of any one of Items 156 to 189, wherein p is 2 to 8.

[0575] Item 191. The antibody-drug conjugate of any one of Items 156 to 190, wherein p is 4 to 8.

[0576] Item 192. The antibody-drug conjugate of any one of Items 156 to 191, wherein p is 4.

[0577] Item 193. The antibody-drug conjugate of any one of Items 156 to 191, wherein p is 8.

[0578] Item 194. A composition comprising multiple copies of the antibody-drug conjugate of any one of Items 1 to 193, wherein the average p of the antibody-drug conjugate in the composition is about 3.5 to about 5.5.

[0579] Item 195. The composition of Item 194, wherein the average p of the antibody-drug conjugate in the composition is about 4.

[0580] Item 196. A composition comprising multiple copies of the antibody-drug conjugate of any one of Items 1 to 193, wherein the average p of the antibody-drug conjugate in the composition is about 7 to about 9.

[0581] Item 197. The composition of Item 196, wherein the average p of the antibody-drug conjugate in the composition is about 8.

[0582] Item 198. 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 193 or a composition as described in any one of Items 194 to 197.

[0583] Item 199. The method of Item 198, wherein the neoplastic disorder is a hematological malignancy or a solid tumor.

[0584] Item 200. The method of Item 198 or Item 199, wherein the neoplastic disorder is a hematological malignancy.

[0585] Item 201. The method of Item 199 or Item 200, wherein the hematological malignancy is selected from acute myeloid leukemia and multiple myeloma.

[0586] Item 202. The method of Item 198 or Item 199, wherein the neoplastic disorder is a solid tumor.

[0587] Item 203. The method of Item 199 or Item 202, wherein the solid tumor is selected from breast cancer, gastric cancer, prostate cancer, ovarian cancer, lung cancer, uterine cancer, salivary duct carcinoma, melanoma, colon cancer, cervical cancer, pancreatic cancer, renal cancer, colorectal cancer and esophageal cancer.

[0588] Item 204. The method of any one of Items 198 to 203, wherein 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.

[0589] Item 205. The method of any one of Items 198 to 204, wherein the subject has one or more neoplastic cells expressing the target antigen.

[0590] Item 206. The method of Item 205, wherein the target antigen is HER2.

[0591] Item 207. The method of Item 206, wherein the one or more neoplastic cells are derived from a HER2-expressing breast cancer, ovarian cancer, gastric cancer, lung cancer, uterine cancer, osteosarcoma, or salivary duct carcinoma.

[0592] Item 208. The method of Item 207, wherein the lung cancer is lung adenocarcinoma and / or the uterine cancer is uterine serous endometrial carcinoma.

[0593] Item 209. The method of any one of Items 206 to 208, wherein the subject is unresponsive or responds poorly to treatment with (a) an anti-HER2 antibody when administered alone and / or (b) a splicing regulator when administered alone.

[0594] Item 210. The method of any one of Items 206 to 209, wherein the subject is intolerant, unresponsive, or poorly responsive to treatment with the splicing regulator when administered alone.

[0595] Item 211. A method as described in Item 205, wherein the target antigen is CD138.

[0596] Item 212. The method of Item 211, wherein the one or more neoplastic cells are derived from a multiple myeloma expressing CD138.

[0597] Item 213. The method of Item 211 or Item 212, wherein the subject is unresponsive or responds poorly to treatment with (a) an anti-CD138 antibody when administered alone and / or (b) a splicing regulator when administered alone.

[0598] Item 214. The method of any one of Items 211 to 213, wherein the subject is intolerant, unresponsive, or poorly responsive to treatment with the splicing regulator when administered alone.

[0599] Item 215. The method of Item 205, wherein the target antigen is EPHA2.

[0600] Item 216. The method of Item 215, wherein the one or more neoplastic cells are derived from a breast cancer, prostate cancer, ovarian cancer, lung cancer, melanoma, colon cancer, or esophageal cancer that expresses EPHA2.

[0601] Item 217. The method of Item 215 or Item 216, wherein the subject is unresponsive or responds poorly to treatment with (a) an anti-EPHA2 antibody when administered alone and / or (b) a splicing regulator when administered alone.

[0602] Item 218. The method of any one of Items 215 to 217, wherein the subject is intolerant, unresponsive, or poorly responsive to treatment with the splicing regulator when administered alone.

[0603] Item 219. 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 an antibody-drug conjugate as described in any one of Items 1 to 193 or a composition as described in any one of Items 194 to 197.

[0604] Item 220. The method of Item 219, wherein treatment with the 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.

[0605] Item 221. The method of Item 219 or Item 220, wherein the tumor comprises one or more neoplastic cells that express the target antigen.

[0606] Item 222. The method of Item 221, wherein the target antigen is HER2.

[0607] Item 223. The method of Item 222, wherein the one or more neoplastic cells are derived from a HER2-expressing breast cancer, ovarian cancer, gastric cancer, lung cancer, uterine cancer, osteosarcoma, or salivary duct carcinoma.

[0608] Item 224. The method of Item 223, wherein the lung cancer is lung adenocarcinoma and / or the uterine cancer is uterine serous endometrial carcinoma.

[0609] Item 225. The method of any one of Items 222 to 224, 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.

[0610] Item 226. A method as described in Item 221, wherein the target antigen is CD138.

[0611] Item 227. The method of Item 226, wherein the one or more neoplastic cells are derived from a multiple myeloma expressing CD138.

[0612] Item 228. The method of Item 226 or Item 227, 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.

[0613] Item 229. The method of Item 221, wherein the target antigen is EPHA2.

[0614] Item 230. The method of Item 229, wherein the one or more neoplastic cells are derived from a breast cancer, prostate cancer, ovarian cancer, lung cancer, melanoma, colon cancer, or esophageal cancer that expresses EPHA2.

[0615] Item 231. The method of Item 229 or Item 230, 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.

[0616] Item 232. A method for determining whether a subject having or suspected of having a neoplastic disorder will respond to treatment with an antibody-drug conjugate as described in any one of Items 1 to 193 or a composition as described in any one of Items 194 to 197, the method comprising providing a biological sample from the subject and contacting the biological sample with the antibody-drug conjugate as described in any one of Items 1 to 193 or a composition as described in any one of Items 194 to 197.

[0617] Item 233. A method as described in Item 232, wherein the biological sample is a tumor sample.

[0618] Item 234. The method of Item 233, wherein the tumor sample is a tumor biopsy or a blood sample.

[0619] Item 235. A method as described in Item 234, wherein the blood sample is selected from blood, a blood fraction, or cells obtained from the blood or a blood fraction.

[0620] Item 236. The method of any one of Items 232 to 235, wherein the subject has one or more neoplastic cells expressing the target antigen.

[0621] Item 237. The method of Item 236, wherein the target antigen is HER2.

[0622] Item 238. The method of Item 237, wherein the one or more neoplastic cells are derived from a HER2-expressing breast cancer, ovarian cancer, gastric cancer, lung cancer, uterine cancer, osteosarcoma, or salivary duct carcinoma.

[0623] Item 239. The method of Item 238, wherein the lung cancer is lung adenocarcinoma and / or the uterine cancer is uterine serous endometrial carcinoma.

[0624] Item 240. A method as described in Item 236, wherein the target antigen is CD138.

[0625] Item 241. The method of Item 240, wherein the one or more neoplastic cells are derived from a multiple myeloma expressing CD138.

[0626] Item 242. A method as described in Item 236, wherein the target antigen is EPHA2.

[0627] Item 243. The method of Item 242, wherein the one or more neoplastic cells are derived from a breast cancer, prostate cancer, ovarian cancer, lung cancer, melanoma, colon cancer, or esophageal cancer that expresses EPHA2.

[0628] Item 244. The antibody-drug conjugate of any one of Items 1 to 193 or the composition of any one of Items 194 to 197 for use in treating a neoplastic disorder.

[0629] Item 245. An antibody-drug conjugate for use as described in Item 244, wherein the neoplastic disorder is characterized by one or more neoplastic cells expressing the target antigen.

[0630] Item 246. An antibody-drug conjugate for use as described in Item 245, wherein the target antigen is HER2.

[0631] Item 247. An antibody-drug conjugate for use as described in Item 246, wherein the neoplastic disorder is HER2-expressing breast cancer, ovarian cancer, gastric cancer, lung cancer, uterine cancer, osteosarcoma, or salivary duct carcinoma.

[0632] Item 248. The antibody-drug conjugate of Item 247, wherein the lung cancer is lung adenocarcinoma and / or the uterine cancer is uterine serous endometrial carcinoma.

[0633] Item 249. An antibody-drug conjugate for use as described in Item 245, wherein the target antigen is CD138.

[0634] Item 250. An antibody-drug conjugate for use as described in Item 249, wherein the neoplastic disorder is CD138-expressing multiple myeloma.

[0635] Item 251. An antibody-drug conjugate for use as described in Item 245, wherein the target antigen is EPHA2.

[0636] Item 252. An antibody-drug conjugate for use as described in Item 251, wherein the neoplastic disorder is EPHA2-expressing breast cancer, prostate cancer, ovarian cancer, lung cancer, melanoma, colon cancer, or esophageal cancer.

[0637] Item 253. Use of an antibody-drug conjugate as described in any one of Items 1 to 193 or a composition as described in any one of Items 194 to 197 for treating a neoplastic disorder.

[0638] Item 254. The use of Item 253, wherein the neoplastic disorder is characterized by one or more neoplastic cells expressing the target antigen.

[0639] Item 255. The use as described in Item 254, wherein the target antigen is HER2.

[0640] Item 256. The use of Item 255, wherein the neoplastic disorder is HER2-expressing breast cancer, ovarian cancer, gastric cancer, lung cancer, uterine cancer, osteosarcoma, or salivary duct carcinoma.

[0641] Item 257. The use of Item 256, wherein the lung cancer is lung adenocarcinoma and / or the uterine cancer is uterine serous endometrial carcinoma.

[0642] Item 258. The use as described in Item 254, wherein the target antigen is CD138.

[0643] Item 259. The use of Item 258, wherein the neoplastic disorder is multiple myeloma expressing CD138.

[0644] Item 260. The use as described in Item 254, wherein the target antigen is EPHA2.

[0645] Item 261. The use of Item 260, wherein the neoplastic disorder is EPHA2-expressing breast cancer, prostate cancer, ovarian cancer, lung cancer, melanoma, colon cancer, or esophageal cancer.

[0646] Item 262. Use of an antibody-drug conjugate as described in any one of Items 1 to 193 or a composition as described in any one of Items 194 to 197 in a method for the manufacture of a medicament for treating a neoplastic disorder.

[0647] Item 263. The use of Item 262, wherein the neoplastic disorder is characterized by one or more neoplastic cells expressing the target antigen.

[0648] Item 264. The use as described in Item 263, wherein the target antigen is HER2.

[0649] Item 265. The use of Item 264, wherein the neoplastic disorder is HER2-expressing breast cancer, ovarian cancer, gastric cancer, lung cancer, uterine cancer, osteosarcoma, or salivary duct carcinoma.

[0650] Item 266. The use of Item 265, wherein the lung cancer is lung adenocarcinoma and / or the uterine cancer is uterine serous endometrial carcinoma.

[0651] Item 267. The use as described in Item 263, wherein the target antigen is CD138.

[0652] Item 268. The use of Item 267, wherein the neoplastic disorder is multiple myeloma expressing CD138.

[0653] Item 269. The use as described in Item 263, wherein the target antigen is EPHA2.

[0654] Item 270. The use of Item 269, wherein the neoplastic disorder is EPHA2-expressing breast cancer, prostate cancer, ovarian cancer, lung cancer, melanoma, colon cancer, or esophageal cancer.

[0655] Item 271. A pharmaceutical composition comprising the antibody-drug conjugate described in any one of Items 1 to 193 or the composition described in any one of Items 194 to 197, and a pharmaceutically acceptable carrier.

[0656] Item 272. A method of producing an antibody-drug conjugate as described in any one of Items 1 to 193, the method comprising reacting the antibody or antigen-binding fragment with a linker conjugated to a splicing regulator under conditions that allow conjugation.

[0657] Item 273. A compound having formula (III):

[0658] or a pharmaceutically acceptable salt thereof, wherein:

[0659] R 1 is selected from the group consisting of absence, hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group, a -OC(=O)-(C1-C6 alkyl) group, and -CD3;

[0660] R 2 Not present or a joint;

[0661] R 3 is selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group and a -OC(=O)-(C1-C6 alkyl) group; and

[0662] R 4 、R 5 and R 8 are each independently selected from hydrogen, a hydroxyl group, an —O—(C 1 -C 6 alkyl) group, a —OC(═O)—(C 1 -C 6 alkyl) group, and a C 1 -C 6 alkyl group;

[0663] R 6 and R 7 are each independently selected from hydrogen, -OR 17 、-OC(=O)-R 17 、-OC(=O)-NR 15 R 16 , C1-C6 alkyl group, -NR 15 R 16 and joints;

[0664] R 15 and R 16 are each independently selected from hydrogen, R 17 、-C(=O)-R 17 and -C(=O)-OR 17;

[0665] R 17 is selected from hydrogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a benzyl group and a C3-C8 heterocyclyl group;

[0666] Z" is selected from

[0667] where R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 15 、R 16 and R 17 Each is independently substituted by 0 to 3 groups independently selected from the following: halogen, hydroxyl group, C1-C6 alkyl, -O-(C1-C6 alkyl) group, -NR 15 R 16 , a C3-C8 cycloalkyl group, a C1-C6 alkylhydroxyl group, a C1-C6 alkylalkoxy group, a benzyl group and a C3-C8 heterocyclyl group;

[0668] where R 6 and R 7 At least one of is hydrogen; and

[0669] If R 2 is a connector, then R 6 and R 7 are not joints, and if R 6 or R 7 is a connector, then R 2 Does not exist.

[0670] Item 274. A compound having formula (V):

[0671] or a pharmaceutically acceptable salt thereof, wherein:

[0672] R 1 is selected from the group consisting of absence, hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group, a -OC(=O)-(C1-C6 alkyl) group, and -CD3;

[0673] R 2 Not present or a joint;

[0674] R 3 is selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group and a -OC(=O)-(C1-C6 alkyl) group; and

[0675] R 4 、R 5 and R 8 are each independently selected from hydrogen, a hydroxyl group, an —O—(C 1 -C 6 alkyl) group, a —OC(═O)—(C 1 -C 6 alkyl) group, and a C 1 -C 6 alkyl group;

[0676] R 6 and R 7 are each independently selected from hydrogen, -OR 17 、-OC(=O)-R 17 、-OC(=O)-NR 15 R 16 , C1-C6 alkyl group, -NR 15 R 16 and joints;

[0677] R 15 and R 16 are each independently selected from hydrogen, R 17 、-C(=O)-R 17 and -C(=O)-OR 17 ;and

[0678] R 17 is selected from hydrogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a benzyl group and a C3-C8 heterocyclyl group;

[0679] where R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 15 、R 16 and R 17 Each is independently substituted by 0 to 3 groups independently selected from the following: halogen, hydroxyl group, C1-C6 alkyl, -O-(C1-C6 alkyl) group, -NR 15 R 16 , a C3-C8 cycloalkyl group, a C1-C6 alkylhydroxyl group, a C1-C6 alkylalkoxy group, a benzyl group and a C3-C8 heterocyclyl group;

[0680] where R 6 and R 7 At least one of is hydrogen; and

[0681] If R 2 is a connector, then R 6 and R 7 are not joints, and if R 6 or R 7 is a connector, then R 2 Does not exist.

[0682] Item 275. A compound having formula (VII):

[0683] or a pharmaceutically acceptable salt thereof, wherein:

[0684] R 1 and R 9 Each is independently selected from the group consisting of absence, hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group, a -OC(=O)-(C1-C6 alkyl) group, and -CD3;

[0685] R 2 Not present or a joint;

[0686] R 3 is selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group and a -OC(=O)-(C1-C6 alkyl) group;

[0687] R 4 、R 5 and R 8 are each independently selected from hydrogen, a hydroxyl group, an —O—(C 1 -C 6 alkyl) group, a —OC(═O)—(C 1 -C 6 alkyl) group, and a C 1 -C 6 alkyl group;

[0688] R 6 and R 7 are each independently selected from hydrogen, -OR 17 、-OC(=O)-R 17 、-OC(=O)-NR 15 R 16 , C1-C6 alkyl group, -NR 15 R 16 and joints;

[0689] R 10 is selected from hydrogen, a C1-C6 alkyl group, a -C(=O)-(C1-C6 alkyl) group and -CD3;

[0690] R 15 and R 16 are each independently selected from hydrogen, R 17 、-C(=O)-R 17 and -C(=O)-OR 17 ;

[0691] R 17 is selected from hydrogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a benzyl group and a C3-C8 heterocyclyl group; and

[0692] a is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0693] where R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 15 、R 16 and R 17 Each is independently substituted by 0 to 3 groups independently selected from the following: halogen, hydroxyl group, C1-C6 alkyl group, -O-(C1-C6 alkyl) group, -NR 15 R 16 , a C3-C8 cycloalkyl group, a C1-C6 alkylhydroxyl group, a C1-C6 alkylalkoxy group, a benzyl group and a C3-C8 heterocyclyl group;

[0694] where R 6 and R 7 At least one of them is hydrogen;

[0695] If R 2 is a connector, then R 6 and R 7 are not joints, and if R 6 or R 7 is a connector, then R 2 does not exist; and

[0696] where R 1 and R 9 Cannot exist at the same time.

[0697] Item 276. A compound having formula (IX):

[0698] or a pharmaceutically acceptable salt thereof, wherein:

[0699] R 1 is selected from the group consisting of absence, hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group, a -OC(=O)-(C1-C6 alkyl) group, and -CD3;

[0700] R 2 It is a joint;

[0701] R 3 is selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group and a -OC(=O)-(C1-C6 alkyl) group;

[0702] R 4 is selected from hydrogen, a hydroxyl group, an —O—(C 1 -C 6 alkyl) group, a —OC(═O)—(C 1 -C 6 alkyl) group, and a C 1 -C 6 alkyl group;

[0703] R 10 selected from 3 to 10 membered carbocyclic rings and 3 to 10 membered heterocyclic rings, each of which is surrounded by 0 to 3 R a Substitute, where each R a independently selected from halogen, C1-C6 alkyl group, -O-(C1-C6)alkyl group, C1-C6 alkylalkoxy group, C1-C6 alkylhydroxyl group, -S(=O) w -(4- to 7-membered heterocyclic ring), 4- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring;

[0704] R 15 and R 16 are each independently selected from hydrogen, R 17 、-C(=O)-R 17 and -C(=O)-OR 17 ;and

[0705] R 17 is selected from hydrogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a benzyl group and a C3-C8 heterocyclyl group;

[0706] where R 1 、R 2 、R3 、R 4 、R 10 、R 15 、R 16 and R 17 Each is independently substituted by 0 to 3 groups independently selected from the following: halogen, hydroxyl group, C1-C6 alkyl group, -O-(C1-C6 alkyl) group, -NR 15 R 16 , a C3-C8 cycloalkyl group, a C1-C6 alkylhydroxy group, a C1-C6 alkylalkoxy group, a benzyl group, and a C3-C8 heterocyclyl group; and

[0707] Each R a is independently substituted with 0 to 3 groups independently selected from the group consisting of halogen, hydroxyl, -NR 15 R 16 , C1-C6 alkyl group, -(C=O)-(C1-C6 alkyl) group, -(C=O)-(C1-C6 alkyl)-(C3-C 10 heterocyclyl) group, -S(=O) w -(C3-C8 heterocyclyl group and C1-C6 alkylcarboxylic acid group, each of which is substituted by 0, 1 or 2 groups independently selected from the following groups: halogen, hydroxyl group, -NR 15 R 16 and C1-C3 alkyl groups.

[0708] Item 277. A compound selected from the group consisting of

[0709] Compounds and pharmaceutically acceptable salts thereof.

[0710] Item 278. A pharmaceutical composition comprising the compound as described in Item 277 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0711] Item 279. A compound selected from the group consisting of

[0712] Compounds and pharmaceutically acceptable salts thereof.

[0713] Item 280. A pharmaceutical composition comprising the compound as described in Item 279 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0714] Item 281. A compound selected from the group consisting of

[0715] Compounds and pharmaceutically acceptable salts thereof.

[0716] Item 282. A pharmaceutical composition comprising the compound as described in Item 281 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0717] Item 283. A compound selected from the group consisting of

[0718] Compounds and pharmaceutically acceptable salts thereof.

[0719] Item 284. A pharmaceutical composition comprising the compound as described in Item 283 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0720] Item 285. A compound selected from the group consisting of

[0721] Compounds and pharmaceutically acceptable salts thereof.

[0722] Item 286. A pharmaceutical composition comprising the compound as described in Item 285 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0723] Item 287. A compound selected from the group consisting of

[0724] Compounds and pharmaceutically acceptable salts thereof.

[0725] Item 288. A pharmaceutical composition comprising the compound as described in Item 287 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0726] Item 289. A compound selected from the group consisting of

[0727] Compounds and pharmaceutically acceptable salts thereof.

[0728] Item 290. A pharmaceutical composition comprising the compound as described in Item 289 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0729] Item 291. A compound selected from the group consisting of

[0730] Compounds and pharmaceutically acceptable salts thereof.

[0731] Item 292. A pharmaceutical composition comprising the compound as described in Item 291 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0732] Item 293. A compound selected from the group consisting of

[0733] Compounds and pharmaceutically acceptable salts thereof.

[0734] Item 294. A pharmaceutical composition comprising the compound as described in Item 293 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0735] Item 295. A compound selected from the group consisting of

[0736] Compounds and pharmaceutically acceptable salts thereof.

[0737] Item 296. A pharmaceutical composition comprising the compound as described in Item 295 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0738] Item 297. A compound selected from the group consisting of

[0739] Compounds and pharmaceutically acceptable salts thereof.

[0740] Item 298. A pharmaceutical composition comprising the compound as described in Item 297 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0741] Item 299. A compound selected from the group consisting of

[0742] Compounds and pharmaceutically acceptable salts thereof.

[0743] Item 300. A pharmaceutical composition comprising the compound as described in Item 299 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0744] Item 301. 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 a compound or pharmaceutical composition as described in any one of Items 273 to 300.

[0745] Item 302. 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 a compound or pharmaceutical composition as described in any one of Items 273 to 300.

[0746] Item 303. A method for inducing at least one neoantigen, the method comprising contacting a neoplastic cell with an effective amount of a splicing regulator, an antibody-drug conjugate as described in any one of Items 1 to 193, or a composition as described in any one of Items 194 to 197, thereby inducing the production of at least one neoantigen.

[0747] Item 304. A method as described in Item 303, wherein the at least one neoantigen comprises an amino acid sequence of any one of SEQ ID NOs: 37-65.

[0748] Item 305. A method as described in Item 304, wherein the at least one neoantigen comprises the amino acid sequence of SEQ ID NO:37.

[0749] Item 306. A method as described in Item 304, wherein the at least one neoantigen comprises the amino acid sequence of SEQ ID NO:39.

[0750] Item 307. A method as described in Item 304, wherein the at least one neoantigen comprises an amino acid sequence of any one of SEQ ID NOs:46-49.

[0751] Item 308. The method of any one of Items 303 to 307, wherein the neoplastic cell is present in an in vitro cell culture.

[0752] Item 309. The method of Item 308, wherein the neoplastic cells are obtained from a subject.

[0753] Item 310. The method of any one of Items 303 to 307, wherein the neoplastic cell is present in a subject.

[0754] Item 311. The method of any one of Items 303 to 310, wherein the neoplastic cell is derived from a hematological malignancy or a solid tumor.

[0755] Item 312. The method of Item 311, wherein the hematological malignancy is selected from B-cell malignancies, leukemias, lymphomas, and myelomas.

[0756] Item 313. The method of Item 311 or Item 312, wherein the hematological malignancy is selected from acute myeloid leukemia and multiple myeloma.

[0757] Item 314. The method of Item 311, wherein the solid tumor is selected from breast cancer, gastric cancer, prostate cancer, ovarian cancer, lung cancer, uterine cancer, salivary duct cancer, melanoma, colon cancer, cervical cancer, pancreatic cancer, renal cancer, colorectal cancer and esophageal cancer.

[0758] Item 315. A method for inducing at least one neoantigen and / or 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 a splicing regulator, an antibody-drug conjugate as described in any one of Items 1 to 193, or a composition as described in any one of Items 194 to 197.

[0759] Item 316. 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 a splicing regulator, an antibody-drug conjugate as described in any one of Items 1 to 193, or a composition as described in any one of Items 194 to 197, wherein administration of the splicing regulator, antibody-drug conjugate, or composition induces at least one neoantigen and / or T cell response.

[0760] Item 317. A method as described in Item 315 or Item 316, wherein the at least one new antigen comprises the amino acid sequence of any one of SEQ ID NO:37-65.

[0761] Item 318. A method as described in Item 317, wherein the at least one neoantigen comprises the amino acid sequence of SEQ ID NO:37.

[0762] Item 319. A method as described in Item 317, wherein the at least one neoantigen comprises the amino acid sequence of SEQ ID NO:39.

[0763] Item 320. A method as described in Item 317, wherein the at least one neoantigen comprises an amino acid sequence of any one of SEQ ID NOs:46-49.

[0764] Item 321. The method of any one of Items 315 to 320, wherein the amount of the splicing regulator, antibody-drug conjugate, or composition administered is reduced due to the induction of at least one neoantigen and / or T cell response compared to a standard dose of the splicing regulator, antibody-drug conjugate, or composition.

[0765] Item 322. The method of any one of Items 315 to 321, wherein the amount of the splicing regulator, antibody-drug conjugate, or composition administered is reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75% or 90% compared to a standard dose of the splicing regulator, antibody-drug conjugate, or composition.

[0766] Item 323. A method as described in any of Items 315 to 322, wherein the frequency of administration of the splicing regulator, antibody-drug conjugate, or composition is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75% or 90% less than the standard dosing regimen of the splicing regulator, antibody-drug conjugate, or composition.

[0767] Item 324. The method of any one of Items 315 to 323, wherein the amount and / or dosage of the splicing regulator, antibody-drug conjugate, or composition administered results in lower systemic toxicity and / or improved tolerability.

[0768] Item 325. The method of any one of Items 315 to 324, further comprising administering at least one additional therapy.

[0769] Item 326. The method of Item 325, wherein the amount of the splicing regulator, antibody-drug conjugate, composition, and / or the at least one additional therapy administered is reduced due to the induction of at least one neoantigen and / or T cell response compared to the standard dose of the splicing regulator, antibody-drug conjugate, composition, and / or the at least one additional therapy.

[0770] Item 327. The method of Item 325 or Item 326, wherein the amount of the splicing regulator, 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% compared to the standard dose of the splicing regulator, antibody-drug conjugate, composition, and / or the at least one additional therapy.

[0771] Item 328. The method of any one of Items 325 to 327, wherein the frequency of administration of the splicing regulator, antibody-drug conjugate, composition, and / or the at least one additional therapy is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75% or 90% less than the standard dosing regimen of the splicing regulator, antibody-drug conjugate, composition, and / or the at least one additional therapy.

[0772] Item 329. The method of any one of Items 325 to 328, wherein the amount and / or dosage of the splicing regulator, antibody-drug conjugate, composition, and / or the at least one additional therapy administered results in lower systemic toxicity and / or improved tolerability.

[0773] Item 330. The method of any one of Items 325 to 329, wherein administration of the splicing regulator, antibody-drug conjugate, or composition is initiated prior to administration of the at least one additional therapy.

[0774] Item 331. The method of any one of Items 325 to 329, wherein administration of the splicing regulator, antibody-drug conjugate, or composition is initiated after administration of the at least one additional therapy.

[0775] Item 332. The method of any one of Items 325 to 329, wherein administration of the splicing regulator, antibody-drug conjugate, or composition is initiated simultaneously with administration of the at least one additional therapy.

[0776] Item 333. The method of any one of Items 315 to 332, wherein after the initial administration, the splicing regulator, antibody-drug conjugate, or composition is administered repeatedly at least once.

[0777] Item 334. The method of Item 333, wherein the amount of the splicing regulator, antibody-drug conjugate, or composition used for repeated administration is reduced compared to the amount used for initial administration.

[0778] Item 335. The method of Item 333 or Item 334, wherein the amount of the splicing regulator, antibody-drug conjugate, or composition for repeated administration is reduced compared to a standard dose of the splicing regulator, antibody-drug conjugate, or composition.

[0779] Item 336. The method of any one of Items 333 to 335, wherein the amount of the splicing regulator, 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 splicing regulator, antibody-drug conjugate, or composition.

[0780] Item 337. The method of any one of Items 325 to 336, wherein after the initial administration, the at least one additional therapy is repeated at least once.

[0781] Item 338. The method of Item 337, wherein the amount of the at least one additional therapy for repeated administration is reduced compared to the amount for initial administration.

[0782] Item 339. The method of Item 337 or Item 338, 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.

[0783] Item 340. The method of any one of Items 337 to 339, 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.

[0784] Item 341. The method of any one of Items 337 to 340, wherein repeated administration of the splicing regulator, antibody-drug conjugate, or composition is performed concurrently with repeated administration of the at least one additional therapy.

[0785] Item 342. The method of any one of Items 337 to 340, wherein repeated administration of the splicing regulator, antibody-drug conjugate, or composition is sequential or staggered with repeated administration of the at least one additional therapy.

[0786] Item 343. The method of any one of Items 325 to 342, wherein the at least one additional therapy comprises administration of a checkpoint inhibitor.

[0787] Item 344. The method of Item 343, wherein the subject is intolerant, unresponsive, or poorly responsive to the checkpoint inhibitor when administered alone.

[0788] Item 345. The method of Item 343 or Item 344, wherein the checkpoint inhibitor targets CTLA4, PD1, PDL1, OX40, CD40, GITR, LAG3, TIM3 and / or KIR.

[0789] Item 346. A method as described in any of Items 343 to 345, wherein the checkpoint inhibitor targets CTLA4, OX40, CD40 and / or GITR.

[0790] Item 347. A method as described in any one of Items 343 to 346, wherein the checkpoint inhibitor comprises a cytotoxic T lymphocyte-associated antigen 4 pathway (CTLA4) inhibitor.

[0791] Item 348. The method of Item 347, wherein the CTLA4 inhibitor is an anti-CTLA4 antibody.

[0792] Item 349. The method of Item 348, wherein the anti-CTLA4 antibody is ipilimumab.

[0793] Item 350. The method of any one of Items 343 to 346, wherein the checkpoint inhibitor comprises a programmed death-1 pathway (PD1) inhibitor.

[0794] Item 351. The method of Item 350, wherein the PD1 inhibitor is an anti-PD1 antibody.

[0795] Item 352. The method of Item 351, wherein the anti-PD1 antibody is nivolumab.

[0796] Item 353. The method of Item 350, wherein the PD1 inhibitor is an anti-PDL1 antibody.

[0797] Item 354. The method of Item 353, wherein the anti-PDL1 antibody is atezolizumab.

[0798] Item 355. The method of any one of Items 343 to 346, wherein the checkpoint inhibitor comprises a CTLA4 inhibitor and a PD1 inhibitor.

[0799] Item 356. The method of Item 355, wherein the CTLA4 inhibitor is an anti-CTLA4 antibody.

[0800] Item 357. The method of Item 356, wherein the anti-CTLA4 antibody is ipilimumab.

[0801] Item 358. The method of Item 355, wherein the PD1 inhibitor is an anti-PD1 antibody.

[0802] Item 359. The method of Item 358, wherein the anti-PD1 antibody is nivolumab.

[0803] Item 360. The method of Item 355, wherein the PD1 inhibitor is an anti-PDL1 antibody.

[0804] Item 361. The method of Item 360, wherein the anti-PDL1 antibody is atezolizumab.

[0805] Item 362. The method of any one of Items 325 to 342, wherein the at least one additional therapy comprises administering a neoantigen vaccine.

[0806] Item 363. The method of Item 362, wherein the splicing regulator, antibody-drug conjugate, or composition is administered prior to administering the neoantigen vaccine.

[0807] Item 364. The method of Item 362, wherein the splicing regulator, antibody-drug conjugate, or composition is administered after administration of the neoantigen vaccine.

[0808] Item 365. The method of Item 362, wherein the splicing regulator, antibody-drug conjugate, or composition is administered concurrently with administration of the neoantigen vaccine.

[0809] Item 366. The method of any one of Items 362 to 365, wherein after the initial administration, the splicing regulator, antibody-drug conjugate, or composition is administered repeatedly at least once.

[0810] Item 367. The method of Item 366, wherein the amount of the splicing regulator, antibody-drug conjugate, or composition used for repeated administration is reduced compared to the amount used for initial administration.

[0811] Item 368. The method of any one of Items 362 to 367, wherein the neoantigen vaccine comprises at least one neoantigen peptide.

[0812] Item 369. A method as described in Item 368, wherein the length of the at least one neoantigenic peptide ranges from about 10 to about 50 or about 10 to about 35 amino acids.

[0813] Item 370. A method as described in Item 368 or Item 369, wherein the length of the at least one neoantigenic peptide is in the range of about 15 to about 25 amino acids.

[0814] Item 371. The method of any one of Items 368 to 370, wherein the at least one neoantigenic peptide comprises one or more than one neoantigenic sequence.

[0815] Item 372. A method as described in Item 371, wherein the neoantigen sequence is a neoantigen sequence unique to the subject.

[0816] Item 373. A method as described in Item 371, wherein the neoantigen sequence is a universal neoantigen sequence.

[0817] Item 374. The method of any one of Items 371 to 373, wherein the neoantigen sequence comprises the amino acid sequence of any one of SEQ ID NOs: 37-65.

[0818] Item 375. A method as described in Item 374, wherein the new antigen sequence comprises the amino acid sequence of SEQ ID NO:37.

[0819] Item 376. A method as described in Item 374, wherein the new antigen sequence comprises the amino acid sequence of SEQ ID NO:39.

[0820] Item 377. A method as described in Item 374, wherein the new antigen sequence comprises the amino acid sequence of any one of SEQ ID NOs:46-49.

[0821] Item 378. A method as described in any of Items 371 to 373, wherein the neoantigen sequence comprises the amino acid sequence of any one of SEQ ID NOs: 66-93, or the antigenic portion of any one of SEQ ID NOs: 66-93.

[0822] Item 379. A method as described in Item 378, wherein the new antigen sequence comprises the amino acid sequence of SEQ ID NO:66, or the antigenic portion of SEQ ID NO:66.

[0823] Item 380. A method as described in Item 378, wherein the new antigen sequence comprises the amino acid sequence of any one of SEQ ID NOs: 74-77, or the antigenic portion of any one of SEQ ID NOs: 74-77.

[0824] Item 381. A method as described in any of Items 374 to 380, wherein the length of the neoantigen sequence and / or antigen portion ranges from about 10 to about 50, about 10 to about 35, about 15 to about 25, or about 10 to about 20 amino acids.

[0825] Item 382. The method of any one of Items 374 to 381, wherein the neoantigen sequence and / or antigen portion is a personalized neoantigen vaccine for the subject.

[0826] Item 383. A method as described in Item 382, ​​wherein the neoantigen sequence and / or antigen portion has been identified by sequencing at least one neoantigen induced in the subject by administration of an effective amount of the splicing regulator, antibody-drug conjugate, or composition.

[0827] Item 384. A method as described in Item 382 or Item 383, wherein the neoantigen sequence and / or antigen portion is capable of binding to at least one HLA allele expressed in the subject.

[0828] Item 385. The method of any one of Items 374 to 381, wherein the neoantigen sequence and / or antigen portion is a universal neoantigen vaccine.

[0829] Item 386. A method as described in Item 385, wherein the neoantigen sequence and / or antigen portion 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 subjects in a population of subjects suffering from the neoplastic disorder.

[0830] Item 387. A method as described in Item 385 or Item 386, wherein the neoantigen sequence and / or antigenic portion 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 suffering from the neoplastic disorder.

[0831] Item 388. The method of any one of Items 385 to 387, wherein the at least one neoantigenic peptide comprises a neoantigenic sequence induced by contacting a neoplastic cell with an effective amount of the splicing regulator, antibody-drug conjugate, or composition.

[0832] Item 389. The method of any one of Items 362 to 367, wherein the neoantigen vaccine comprises at least one neoantigen peptide and a pharmaceutically acceptable carrier.

[0833] Item 390. The method of Item 389, wherein the at least one neoantigenic peptide is linked to the pharmaceutically acceptable carrier.

[0834] Item 391. A method as described in Item 389 or Item 390, wherein the pharmaceutically acceptable carrier is selected from a peptide, serum albumin, keyhole limpet hemocyanin, an immunoglobulin, thyroglobulin, ovalbumin, a toxoid or an attenuated toxoid derivative, a cytokine and a chemokine.

[0835] Item 392. The method of any one of Items 389 to 391, wherein the neoantigenic peptide and the pharmaceutically acceptable carrier are covalently linked via a linker.

[0836] Item 393. The method of any one of Items 389 to 391, wherein the neoantigenic peptide and the pharmaceutically acceptable carrier are expressed as a fusion protein.

[0837] Item 394. The method of any one of Items 362 to 367, wherein the neoantigen vaccine comprises at least one neoantigen peptide and a pharmaceutically acceptable diluent.

[0838] Item 395. The method of any one of Items 362 to 367, wherein the neoantigen vaccine comprises at least one neoantigen peptide and a pharmaceutically acceptable adjuvant.

[0839] Item 396. The method of Item 388, wherein the neoplastic cells are present in an in vitro cell culture.

[0840] Item 397. The method of Item 396, wherein the neoplastic cells are obtained from the subject.

[0841] Item 398. The method of Item 388, wherein the neoplastic cells are present in the subject.

[0842] Item 399. The method of any one of Items 362 to 367, wherein the neoantigen vaccine comprises at least one neoantigen mRNA.

[0843] Item 400. A method as described in Item 399, wherein the at least one neoantigen mRNA encodes one or more neoantigen sequences.

[0844] Item 401. The method of Item 400, wherein the neoantigen sequence is a neoantigen sequence that is specific to the subject.

[0845] Item 402. A method as described in Item 400, wherein the neoantigen sequence is a universal neoantigen sequence.

[0846] Item 403. The method of any one of Items 400 to 402, wherein the neoantigen sequence comprises the amino acid sequence of any one of SEQ ID NOs: 37-65.

[0847] Item 404. A method as described in Item 403, wherein the new antigen sequence comprises the amino acid sequence of SEQ ID NO:37.

[0848] Item 405. A method as described in Item 403, wherein the new antigen sequence comprises the amino acid sequence of SEQ IDNO:39.

[0849] Item 406. A method as described in Item 403, wherein the new antigen sequence comprises the amino acid sequence of any one of SEQ ID NOs:46-49.

[0850] Item 407. The method of any one of Items 400 to 402, wherein the neoantigen sequence comprises the amino acid sequence of any one of SEQ ID NOs: 66-93, or the antigenic portion of any one of SEQ ID NOs: 66-93.

[0851] Item 408. A method as described in Item 407, wherein the new antigen sequence comprises the amino acid sequence of SEQ ID NO:66, or the antigenic portion of SEQ ID NO:66.

[0852] Item 409. A method as described in Item 407, wherein the new antigen sequence comprises the amino acid sequence of any one of SEQ ID NOs: 74-77, or the antigenic portion of any one of SEQ ID NOs: 74-77.

[0853] Item 410. A method as described in any of Items 403 to 409, wherein the length of the neoantigen sequence and / or antigen portion is in the range of about 10 to about 50, about 10 to about 35, about 15 to about 25, or about 10 to about 20 amino acids.

[0854] Item 411. The method of any one of Items 403 to 410, wherein the neoantigen sequence and / or antigen portion is a personalized neoantigen vaccine for the subject.

[0855] Item 412. A method as described in Item 411, wherein the neoantigen sequence and / or antigen portion has been identified by sequencing at least one neoantigen induced in the subject by administration of an effective amount of the splicing regulator, antibody-drug conjugate, or composition.

[0856] Item 413. A method as described in Item 411 or Item 412, wherein the new antigen sequence and / or antigen portion is capable of binding to at least one HLA allele expressed in the subject.

[0857] Item 414. The method of any one of Items 403 to 410, wherein the neoantigen sequence and / or antigen portion is a universal neoantigen vaccine.

[0858] Item 415. A method as described in Item 414, wherein the neoantigen sequence and / or antigen portion 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 subjects in a population of subjects suffering from the neoplastic disorder.

[0859] Item 416. A method as described in Item 414 or Item 415, wherein the neoantigen sequence and / or antigenic portion 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 suffering from the neoplastic disorder.

[0860] Item 417. The method of any one of Items 414 to 416, wherein the at least one neoantigen mRNA encodes a neoantigen sequence induced by contacting a neoplastic cell with an effective amount of the splicing regulator, antibody-drug conjugate, or composition.

[0861] Item 418. The method of any one of Items 362 to 367, wherein the neoantigen vaccine comprises at least one neoantigen mRNA and a pharmaceutically acceptable carrier.

[0862] Item 419. The method of Item 418, wherein the at least one neoantigen mRNA is linked to the pharmaceutically acceptable carrier.

[0863] Item 420. The method of Item 418 or Item 419, wherein the pharmaceutically acceptable carrier is selected from a peptide, serum albumin, keyhole limpet hemocyanin, an immunoglobulin, thyroglobulin, ovalbumin, a toxoid or an attenuated toxoid derivative, a cytokine and a chemokine.

[0864] Item 421. The method of any one of Items 362 to 367, wherein the neoantigen vaccine comprises at least one neoantigen mRNA and a pharmaceutically acceptable diluent.

[0865] Item 422. The method of any one of Items 362 to 367, wherein the neoantigen vaccine comprises at least one neoantigen mRNA and a pharmaceutically acceptable adjuvant.

[0866] Item 423. A method as described in any one of Items 399 to 422, wherein the neoantigen mRNA is encapsulated by an encapsulating agent.

[0867] Item 424. The method of Item 423, wherein the encapsulating agent is a liposome.

[0868] Item 425. The method of Item 423, wherein the encapsulating agent is a nanoparticle.

[0869] Item 426. The method of Item 417, wherein the neoplastic cells are present in an in vitro cell culture.

[0870] Item 427. The method of Item 426, wherein the neoplastic cells are obtained from the subject.

[0871] Item 428. The method of Item 417, wherein the neoplastic cells are present in the subject.

[0872] Item 429. The method of any one of Items 325 to 342, wherein the at least one additional therapy comprises administration of a cytokine or a cytokine analog.

[0873] Item 430. The method of Item 429, wherein the subject is intolerant, unresponsive, or poorly responsive to the cytokine or cytokine analog when administered alone.

[0874] Item 431. The method of Item 429 or Item 430, wherein the cytokine or cytokine analog comprises a T cell enhancer.

[0875] Item 432. The method of any one of Items 429 to 431, wherein the cytokine or cytokine analog comprises IL-2, IL-10, IL-12, IL-15, IFNγ and / or TNFα.

[0876] Item 433. The method of any one of Items 325 to 342, wherein the at least one additional therapy comprises administration of engineered tumor-targeted T cells.

[0877] Item 434. The method of any one of Items 315 to 433, further comprising detecting one or more neoantigens and / or T cell responses in the subject after administering the splicing regulator, antibody-drug conjugate, or composition.

[0878] Item 435. The method of Item 434, further comprising continuing to administer the splicing regulator, antibody-drug conjugate, or composition if one or more neoantigens and / or T cell responses are detected.

[0879] Item 436. The method of Item 434 or Item 435, further comprising continuing to administer the splicing regulator, antibody-drug conjugate, or composition at a lower frequency and / or at a reduced dose if one or more neoantigens and / or T cell responses are detected.

[0880] Item 437. The method of any one of Items 434 to 436, wherein detection of one or more neoantigens and / or T cell responses in the subject indicates efficacy of treatment with the splicing regulator, antibody-drug conjugate, or composition.

[0881] Item 438. A method as described in any of Items 315 to 437, wherein the subject has a non-synonymous mutation burden of approximately 150 mutations or fewer.

[0882] Item 439. A method as described in any of Items 315 to 438, wherein the subject has a non-synonymous mutation burden of approximately 100 mutations or fewer.

[0883] Item 440. The method of any one of Items 315 to 439, wherein the subject has a non-synonymous mutation burden of approximately 50 mutations or fewer.

[0884] Item 441. The method of any one of Items 315 to 440, wherein the neoplastic disorder is a hematological malignancy or a solid tumor.

[0885] Item 442. The method of Item 441, wherein the hematological malignancy is selected from B-cell malignancies, leukemias, lymphomas, and myelomas.

[0886] Item 443. The method of Item 441 or Item 442, wherein the hematological malignancy is selected from acute myeloid leukemia and multiple myeloma.

[0887] Item 444. The method of Item 441, wherein the solid tumor is selected from breast cancer, gastric cancer, prostate cancer, ovarian cancer, lung cancer, uterine cancer, salivary duct cancer, melanoma, colon cancer, cervical cancer, pancreatic cancer, renal cancer, colorectal cancer and esophageal cancer.

[0888] Item 445. A method of treating a subject having or suspected of having a neoplastic disorder, the method comprising:

[0889] (a) administering to the subject an effective amount of a splicing regulator, the antibody-drug conjugate of any one of items 1 to 193, or the composition of any one of items 194 to 197, wherein administration of the splicing regulator, antibody-drug conjugate, or composition induces at least one neoantigen and / or T cell response;

[0890] (b) detecting one or more neoantigens and / or T cell responses in the subject after administration of the splicing modulator, antibody-drug conjugate, or composition; and

[0891] (c) continuing to administer the splicing modulator, antibody-drug conjugate, or composition if one or more neoantigens and / or T cell responses are detected.

[0892] Item 446. The method of Item 445, wherein detection of one or more neoantigens and / or T cell responses in the subject indicates efficacy of treatment with the splicing regulator, antibody-drug conjugate, or composition.

[0893] Item 447. A method as described in Item 445 or Item 446, wherein the one or more new antigens comprise the amino acid sequence of any one of SEQ ID NOs:37-65.

[0894] Item 448. A method as described in Item 447, wherein the one or more new antigens comprise the amino acid sequence of SEQ ID NO:37.

[0895] Item 449. A method as described in Item 447, wherein the one or more new antigens comprise the amino acid sequence of SEQ ID NO:39.

[0896] Item 450. A method as described in Item 447, wherein the one or more new antigens comprise the amino acid sequence of any one of SEQ ID NOs:46-49.

[0897] Item 451. A method of treating a subject having or suspected of having a neoplastic disorder, the method comprising administering to the subject an effective amount of a splicing regulator, an antibody-drug conjugate as described in any one of Items 1 to 193, or a composition as described in any one of Items 194 to 197; and at least one additional therapy.

[0898] Item 452. The method of Item 451, 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.

[0899] Item 453. The method of Item 451 or Item 452, wherein administration of the splicing regulator, antibody-drug conjugate, or composition induces at least one neoantigen and / or T cell response.

[0900] Item 454. The method of any one of Items 451 to 453, wherein the amount of the splicing regulator, 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 splicing regulator, antibody-drug conjugate, or composition, and / or the at least one additional therapy.

[0901] Item 455. The method of any one of Items 451 to 454, wherein the frequency of administration of the splicing regulator, antibody-drug conjugate, or composition, and / or the at least one additional therapy is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75% or 90% less than the standard dosing regimen of the splicing regulator, antibody-drug conjugate, or composition, and / or the at least one additional therapy.

[0902] Item 456. The method of any one of Items 451 to 455, wherein the amount and / or dosage of the splicing regulator, antibody-drug conjugate, or composition, and / or the at least one additional therapy administered results in lower systemic toxicity and / or improved tolerability.

[0903] Item 457. The method of any one of Items 451 to 456, wherein administration of the splicing regulator, antibody-drug conjugate, or composition is initiated prior to administration of the at least one additional therapy.

[0904] Item 458. The method of any one of Items 451 to 456, wherein administration of the splicing regulator, antibody-drug conjugate, or composition is initiated after administration of the at least one additional therapy.

[0905] Item 459. The method of any one of Items 451 to 456, wherein administration of the splicing regulator, antibody-drug conjugate, or composition is initiated simultaneously with administration of the at least one additional therapy.

[0906] Item 460. The method of any one of Items 451 to 460, wherein after the initial administration, the splicing regulator, antibody-drug conjugate, or composition is administered repeatedly at least once.

[0907] Item 461. The method of Item 460, wherein the amount of the splicing regulator, antibody-drug conjugate, or composition used for repeated administration is reduced compared to the amount used for initial administration.

[0908] Item 462. The method of Item 460 or Item 461, wherein the amount of the splicing regulator, antibody-drug conjugate, or composition for repeated administration is reduced compared to a standard dose of the splicing regulator, antibody-drug conjugate, or composition.

[0909] Item 463. The method of any one of Items 460 to 462, wherein the amount of the splicing regulator, 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 splicing regulator, antibody-drug conjugate, or composition.

[0910] Item 464. The method of any one of Items 451 to 463, wherein after the initial administration, the at least one additional therapy is repeated at least once.

[0911] Item 465. The method of Item 464, wherein the amount of the at least one additional therapy for repeated administration is reduced compared to the amount for initial administration.

[0912] Item 466. The method of Item 464 or Item 465, 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.

[0913] Item 467. The method of any one of Items 464 to 466, 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.

[0914] Item 468. The method of any one of Items 464 to 467, wherein repeated administration of the splicing regulator, antibody-drug conjugate, or composition is performed concurrently with repeated administration of the at least one additional therapy.

[0915] Item 469. The method of any one of Items 464 to 467, wherein repeated administration of the splicing regulator, antibody-drug conjugate, or composition is sequential or staggered with repeated administration of the at least one additional therapy.

[0916] Item 470. The method of any one of Items 451 to 469, wherein the at least one additional therapy comprises administration of a checkpoint inhibitor.

[0917] Item 471. The method of Item 470, wherein the subject is intolerant, unresponsive, or poorly responsive to the checkpoint inhibitor when administered alone.

[0918] Item 472. The method of Item 470 or Item 471, wherein the checkpoint inhibitor targets CTLA4, PD1, PDL1, OX40, CD40, GITR, LAG3, TIM3 and / or KIR.

[0919] Item 473. A method as described in any of Items 470 to 472, wherein the checkpoint inhibitor targets CTLA4, OX40, CD40 and / or GITR.

[0920] Item 474. A method as described in any one of Items 470 to 473, wherein the checkpoint inhibitor comprises a cytotoxic T lymphocyte-associated antigen 4 pathway (CTLA4) inhibitor.

[0921] Item 475. The method of Item 474, wherein the CTLA4 inhibitor is an anti-CTLA4 antibody.

[0922] Item 476. The method of Item 475, wherein the anti-CTLA4 antibody is ipilimumab.

[0923] Item 477. The method of any one of Items 470 to 473, wherein the checkpoint inhibitor comprises a programmed death-1 pathway (PD1) inhibitor.

[0924] Item 478. The method of Item 477, wherein the PD1 inhibitor is an anti-PD1 antibody.

[0925] Item 479. The method of Item 478, wherein the anti-PD1 antibody is nivolumab.

[0926] Item 480. The method of Item 477, wherein the PD1 inhibitor is an anti-PDL1 antibody.

[0927] Item 481. The method of Item 480, wherein the anti-PDL1 antibody is atezolizumab.

[0928] Item 482. The method of any one of Items 470 to 473, wherein the checkpoint inhibitor comprises a CTLA4 inhibitor and a PD1 inhibitor.

[0929] Item 483. The method of Item 482, wherein the CTLA4 inhibitor is an anti-CTLA4 antibody.

[0930] Item 484. The method of Item 483, wherein the anti-CTLA4 antibody is ipilimumab.

[0931] Item 485. The method of Item 482, wherein the PD1 inhibitor is an anti-PD1 antibody.

[0932] Item 486. The method of Item 485, wherein the anti-PD1 antibody is nivolumab.

[0933] Item 487. The method of Item 482, wherein the PD1 inhibitor is an anti-PDL1 antibody.

[0934] Item 488. The method of Item 487, wherein the anti-PDL1 antibody is atezolizumab.

[0935] Item 489. The method of any one of Items 451 to 469, wherein the at least one additional therapy comprises administration of a neoantigen vaccine.

[0936] Item 490. The method of Item 489, wherein the splicing regulator, antibody-drug conjugate, or composition is administered prior to administering the neoantigen vaccine.

[0937] Item 491. The method of Item 489, wherein the splicing regulator, antibody-drug conjugate, or composition is administered after administration of the neoantigen vaccine.

[0938] Item 492. The method of Item 489, wherein the splicing regulator, antibody-drug conjugate, or composition is administered concurrently with administration of the neoantigen vaccine.

[0939] Item 493. The method of any one of Items 489 to 492, wherein after the initial administration, the splicing regulator, antibody-drug conjugate, or composition is administered repeatedly at least once.

[0940] Item 494. The method of Item 493, wherein the amount of the splicing regulator, antibody-drug conjugate, or composition used for repeated administration is reduced compared to the amount used for initial administration.

[0941] Item 495. The method of any one of Items 489 to 494, wherein the neoantigen vaccine comprises at least one neoantigen peptide.

[0942] Item 496. A method as described in Item 495, wherein the length of the at least one neoantigenic peptide ranges from about 10 to about 50 or about 10 to about 35 amino acids.

[0943] Item 497. A method as described in Item 495 or Item 496, wherein the length of the at least one neoantigenic peptide is in the range of about 15 to about 25 amino acids.

[0944] Item 498. The method of any one of Items 495 to 497, wherein the at least one neoantigenic peptide comprises one or more than one neoantigenic sequence.

[0945] Item 499. A method as described in Item 498, wherein the neoantigen sequence is a neoantigen sequence unique to the subject.

[0946] Item 500. A method as described in Item 498, wherein the neoantigen sequence is a universal neoantigen sequence.

[0947] Item 501. The method of any one of Items 498 to 500, wherein the neoantigen sequence comprises the amino acid sequence of any one of SEQ ID NOs: 37-65.

[0948] Item 502. A method as described in Item 501, wherein the new antigen sequence comprises the amino acid sequence of SEQ ID NO:37.

[0949] Item 503. A method as described in Item 501, wherein the new antigen sequence comprises the amino acid sequence of SEQ ID NO:39.

[0950] Item 504. A method as described in Item 501, wherein the new antigen sequence comprises the amino acid sequence of any one of SEQ ID NOs:46-49.

[0951] Item 505. The method of any one of Items 498 to 500, wherein the neoantigen sequence comprises the amino acid sequence of any one of SEQ ID NOs: 66-93, or the antigenic portion of any one of SEQ ID NOs: 66-93.

[0952] Item 506. A method as described in Item 505, wherein the new antigen sequence comprises the amino acid sequence of SEQ ID NO:66, or the antigenic portion of SEQ ID NO:66.

[0953] Item 507. A method as described in Item 505, wherein the new antigen sequence comprises the amino acid sequence of any one of SEQ ID NOs:74-77, or the antigenic portion of any one of SEQ ID NOs:74-77.

[0954] Item 508. A method as described in any of Items 501 to 507, wherein the length of the neoantigen sequence and / or antigen portion is in the range of about 10 to about 50, about 10 to about 35, about 15 to about 25, or about 10 to about 20 amino acids.

[0955] Item 509. The method of any one of Items 501 to 508, wherein the neoantigen sequence and / or antigen portion is a personalized neoantigen vaccine for the subject.

[0956] Item 510. A method as described in Item 509, wherein the neoantigen sequence and / or antigen portion has been identified by sequencing at least one neoantigen induced in the subject by administration of an effective amount of the splicing regulator, antibody-drug conjugate, or composition.

[0957] Item 511. A method as described in Item 509 or Item 510, wherein the new antigen sequence and / or antigen portion is capable of binding to at least one HLA allele expressed in the subject.

[0958] Item 512. The method of any one of Items 501 to 508, wherein the neoantigen sequence and / or antigen portion is a universal neoantigen vaccine.

[0959] Item 513. A method as described in Item 512, wherein the neoantigen sequence and / or antigen portion 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 subjects in a population of subjects suffering from the neoplastic disorder.

[0960] Item 514. A method as described in Item 512 or Item 513, wherein the neoantigen sequence and / or antigenic portion 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 suffering from the neoplastic disorder.

[0961] Item 515. The method of any one of Items 512 to 514, wherein the at least one neoantigenic peptide comprises a neoantigenic sequence induced by contacting a neoplastic cell with an effective amount of the splicing regulator, antibody-drug conjugate, or composition.

[0962] Item 516. The method of any one of Items 489 to 494, wherein the neoantigen vaccine comprises at least one neoantigen peptide and a pharmaceutically acceptable carrier.

[0963] Item 517. The method of Item 516, wherein the at least one neoantigenic peptide is linked to the pharmaceutically acceptable carrier.

[0964] Item 518. The method of Item 516 or Item 517, wherein the pharmaceutically acceptable carrier is selected from a peptide, serum albumin, keyhole limpet hemocyanin, an immunoglobulin, thyroglobulin, ovalbumin, a toxoid or an attenuated toxoid derivative, a cytokine and a chemokine.

[0965] Item 519. The method of any one of Items 516 to 518, wherein the neoantigenic peptide and the pharmaceutically acceptable carrier are covalently linked via a linker.

[0966] Item 520. The method of any one of Items 516 to 518, wherein the neoantigenic peptide and the pharmaceutically acceptable carrier are expressed as a fusion protein.

[0967] Item 521. The method of any one of Items 489 to 494, wherein the neoantigen vaccine comprises at least one neoantigen peptide and a pharmaceutically acceptable diluent.

[0968] Item 522. The method of any one of Items 489 to 494, wherein the neoantigen vaccine comprises at least one neoantigen peptide and a pharmaceutically acceptable adjuvant.

[0969] Item 523. The method of Item 515, wherein the neoplastic cells are present in an in vitro cell culture.

[0970] Item 524. The method of Item 523, wherein the neoplastic cells are obtained from the subject.

[0971] Item 525. The method of Item 515, wherein the neoplastic cell is present in the subject.

[0972] Item 526. The method of any one of Items 489 to 494, wherein the neoantigen vaccine comprises at least one neoantigen mRNA.

[0973] Item 527. A method as described in Item 526, wherein the at least one neoantigen mRNA encodes one or more neoantigen sequences.

[0974] Item 528. A method as described in Item 527, wherein the neoantigen sequence is a neoantigen sequence unique to the subject.

[0975] Item 529. A method as described in Item 527, wherein the neoantigen sequence is a universal neoantigen sequence.

[0976] Item 530. The method of any one of Items 527 to 529, wherein the neoantigen sequence comprises the amino acid sequence of any one of SEQ ID NOs: 37-65.

[0977] Item 531. A method as described in Item 530, wherein the new antigen sequence comprises the amino acid sequence of SEQ ID NO:37.

[0978] Item 532. A method as described in Item 530, wherein the new antigen sequence comprises the amino acid sequence of SEQ ID NO:39.

[0979] Item 533. A method as described in Item 530, wherein the new antigen sequence comprises the amino acid sequence of any one of SEQ ID NOs:46-49.

[0980] Item 534. The method of any one of Items 527 to 529, wherein the neoantigen sequence comprises the amino acid sequence of any one of SEQ ID NOs: 66-93, or the antigenic portion of any one of SEQ ID NOs: 66-93.

[0981] Item 535. A method as described in Item 534, wherein the new antigen sequence comprises the amino acid sequence of SEQ ID NO:66, or the antigenic portion of SEQ ID NO:66.

[0982] Item 536. A method as described in Item 534, wherein the new antigen sequence comprises the amino acid sequence of any one of SEQ ID NOs:74-77, or the antigenic portion of any one of SEQ ID NOs:74-77.

[0983] Item 537. A method as described in any of Items 530 to 536, wherein the length of the neoantigen sequence and / or antigen portion is in the range of about 10 to about 50, about 10 to about 35, about 15 to about 25, or about 10 to about 20 amino acids.

[0984] Item 538. A method as described in any of Items 530 to 537, wherein the neoantigen sequence and / or antigen portion is a personalized neoantigen vaccine for the subject.

[0985] Item 539. A method as described in Item 538, wherein the neoantigen sequence and / or antigen portion has been identified by sequencing at least one neoantigen induced in the subject by administration of an effective amount of the splicing regulator, antibody-drug conjugate, or composition.

[0986] Item 540. A method as described in Item 538 or Item 539, wherein the neoantigen sequence and / or antigen portion is capable of binding to at least one HLA allele expressed in the subject.

[0987] Item 541. The method of any one of Items 530 to 537, wherein the neoantigen sequence and / or antigen portion is a universal neoantigen vaccine.

[0988] Item 542. A method as described in Item 541, wherein the neoantigen sequence and / or antigen portion 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 subjects in a population of subjects suffering from the neoplastic disorder.

[0989] Item 543. A method as described in Item 541 or Item 542, wherein the neoantigen sequence and / or antigenic portion 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 suffering from the neoplastic disorder.

[0990] Item 544. The method of any one of Items 541 to 543, wherein the at least one neoantigen mRNA encodes a neoantigen sequence induced by contacting the neoplastic cells with an effective amount of the splicing regulator, antibody-drug conjugate, or composition.

[0991] Item 545. The method of any one of Items 489 to 494, wherein the neoantigen vaccine comprises at least one neoantigen mRNA and a pharmaceutically acceptable carrier.

[0992] Item 546. A method as described in Item 545, wherein the at least one neoantigen mRNA is linked to the pharmaceutically acceptable carrier.

[0993] Item 547. A method as described in Item 545 or Item 546, wherein the pharmaceutically acceptable carrier is selected from a peptide, serum albumin, keyhole limpet hemocyanin, an immunoglobulin, thyroglobulin, ovalbumin, a toxoid or an attenuated toxoid derivative, a cytokine and a chemokine.

[0994] Item 548. The method of any one of Items 489 to 494, wherein the neoantigen vaccine comprises at least one neoantigen mRNA and a pharmaceutically acceptable diluent.

[0995] Item 549. The method of any one of Items 489 to 494, wherein the neoantigen vaccine comprises at least one neoantigen mRNA and a pharmaceutically acceptable adjuvant.

[0996] Item 550. A method as described in any one of Items 526 to 549, wherein the neoantigen mRNA is encapsulated by an encapsulating agent.

[0997] Item 551. The method of Item 550, wherein the encapsulating agent is a liposome.

[0998] Item 552. The method of Item 550, wherein the encapsulating agent is a nanoparticle.

[0999] Item 553. The method of Item 544, wherein the neoplastic cells are present in an in vitro cell culture.

[1000] Item 554. The method of Item 553, wherein the neoplastic cells are obtained from the subject.

[1001] Item 555. The method of Item 544, wherein the neoplastic cell is present in the subject.

[1002] Item 556. The method of any one of Items 451 to 469, wherein the at least one additional therapy comprises administration of a cytokine or a cytokine analog.

[1003] Item 557. The method of Item 556, wherein the subject is intolerant, unresponsive, or poorly responsive to the cytokine or cytokine analog when administered alone.

[1004] Item 558. A method as described in Item 556 or Item 557, wherein the cytokine or cytokine analog comprises a T cell enhancer.

[1005] Item 559. The method of any one of Items 556 to 558, wherein the cytokine or cytokine analog comprises IL-2, IL-10, IL-12, IL-15, IFNγ and / or TNFα.

[1006] Item 560. The method of any one of Items 451 to 469, wherein the at least one additional therapy comprises administration of engineered tumor-targeted T cells.

[1007] Item 561. The method of any one of Items 451 to 560, wherein the subject has a non-synonymous mutation burden of approximately 150 mutations or fewer.

[1008] Item 562. A method as described in any of Items 451 to 561, wherein the subject has a non-synonymous mutation burden of approximately 100 mutations or fewer.

[1009] Item 563. The method of any one of Items 451 to 562, wherein the subject has a non-synonymous mutation burden of approximately 50 mutations or fewer.

[1010] Item 564. The method of any one of Items 451 to 563, wherein the neoplastic disorder is a hematological malignancy or a solid tumor.

[1011] Item 565. The method of Item 564, wherein the hematological malignancy is selected from B-cell malignancies, leukemias, lymphomas, and myelomas.

[1012] Item 566. The method of Item 564 or Item 565, wherein the hematological malignancy is selected from acute myeloid leukemia and multiple myeloma.

[1013] Item 567. The method of Item 564, wherein the solid tumor is selected from breast cancer, gastric cancer, prostate cancer, ovarian cancer, lung cancer, uterine cancer, salivary duct cancer, melanoma, colon cancer, cervical cancer, pancreatic cancer, renal cancer, colorectal cancer and esophageal cancer.

[1014] Item 568. A method for identifying at least one neoantigen, the method comprising:

[1015] (a) contacting a neoplastic cell with an effective amount of a splicing regulator, the antibody-drug conjugate of any one of items 1 to 193, or the composition of any one of items 194 to 197;

[1016] (b) detecting at least one alternatively spliced ​​mRNA transcript after contacting the neoplastic cell with the splicing modulator, antibody-drug conjugate, or composition;

[1017] (c) predicting that the at least one alternatively spliced ​​mRNA transcript is translated into at least one peptide; and

[1018] (d) comparing the at least one peptide to a reference proteome, wherein at least one neoantigen is identified if the at least one peptide does not match any peptide in the reference proteome.

[1019] Item 569. A method as described in Item 568, wherein detecting at least one alternatively spliced ​​mRNA transcript includes RNAseq.

[1020] Item 570. The method of Item 568 or Item 569, wherein predicting the translation of the at least one alternatively spliced ​​mRNA transcript comprises quantifying a percent change in splicing (dPSI) value of the at least one transcript.

[1021] Item 571. The method of any one of Items 568 to 570, wherein predicting translation of the at least one alternatively spliced ​​mRNA transcript comprises RiboSeq and / or ribosome profiling.

[1022] Item 572. The method of any one of Items 568 to 571, wherein the method further comprises evaluating the predicted major histocompatibility complex (MHC) binding of the at least one peptide.

[1023] Item 573. A method as described in Item 572, wherein the predicted MHC binding is determined by measuring the raw affinity predicted binding strength of the at least one peptide.

[1024] Item 574. The method of Item 573, wherein a raw affinity predicted binding strength of about 500 nM or greater is indicative of MHC binding.

[1025] Item 575. A method as described in Item 572, wherein the predicted MHC binding is determined by: identifying a distribution of predicted binding strengths for a series of random peptides; and comparing the predicted binding strength of at least one of the peptides to the distribution.

[1026] Item 576. The method of Item 575, wherein the predicted binding strength in the top 2.0% of the distribution indicates weak MHC binding.

[1027] Item 577. The method of Item 575, wherein the predicted binding strength in the top 0.5% of the distribution indicates strong MHC binding.

[1028] Item 578. The method of any one of Items 568 to 577, wherein the neoplastic cell is present in an in vitro cell culture.

[1029] Item 579. The method of Item 578, wherein the neoplastic cells are obtained from the subject.

[1030] Item 580. The method of any one of Items 568 to 577, wherein the neoplastic cell is present in the subject.

[1031] Item 581. The method of any one of Items 568 to 580, further comprising contacting one or more additional neoplastic cells to identify at least one universal neoantigen.

[1032] Item 582. A method for identifying at least one neoantigen, the method comprising:

[1033] (a) contacting a neoplastic cell with an effective amount of a splicing regulator, the antibody-drug conjugate of any one of items 1 to 193, or the composition of any one of items 194 to 197;

[1034] (b) detecting at least one peptide comprising a potential neoantigen sequence after contacting the neoplastic cell with the splicing modulator, antibody-drug conjugate, or composition; and

[1035] (c) comparing the at least one peptide to a reference proteome, wherein at least one neoantigen is identified if the at least one peptide does not match any peptide in the reference proteome.

[1036] Item 583. The method of Item 582, wherein the method further comprises evaluating the predicted major histocompatibility complex (MHC) binding of the at least one peptide.

[1037] Item 584. A method as described in Item 583, wherein the predicted MHC binding is determined by measuring the raw affinity predicted binding strength of the at least one peptide.

[1038] Item 585. The method of Item 584, wherein a raw affinity predicted binding strength of about 500 nM or greater is indicative of MHC binding.

[1039] Item 586. A method as described in Item 583, wherein the predicted MHC binding is determined by: identifying a distribution of predicted binding strengths for a series of random peptides; and comparing the predicted binding strength of at least one of the peptides to the distribution.

[1040] Item 587. The method of Item 586, wherein the predicted binding strength in the top 2.0% of the distribution indicates weak MHC binding.

[1041] Item 588. The method of Item 586, wherein the predicted binding strength in the top 0.5% of the distribution indicates strong MHC binding.

[1042] Item 589. The method of any one of Items 582 to 588, wherein the neoplastic cell is present in an in vitro cell culture.

[1043] Item 590. The method of Item 589, wherein the neoplastic cells are obtained from the subject.

[1044] Item 591. The method of any one of Items 582 to 588, wherein the neoplastic cell is present in the subject.

[1045] Item 592. The method of any one of Items 582 to 591, further comprising contacting one or more additional neoplastic cells to identify at least one universal neoantigen.

[1046] Item 593. A method for producing a neoantigen vaccine, the method comprising:

[1047] (a) identifying at least one neoantigen using the method of any one of items 568 to 592; and

[1048] (b) formulating the at least one neoantigen with a pharmaceutically acceptable carrier, diluent or adjuvant.

[1049] Item 594. A method as described in Item 593, wherein the at least one neoantigen comprises an amino acid sequence of any one of SEQ ID NOs: 37-65.

[1050] Item 595. A method as described in Item 594, wherein the at least one neoantigen comprises the amino acid sequence of SEQ ID NO:37.

[1051] Item 596. A method as described in Item 594, wherein the at least one neoantigen comprises the amino acid sequence of SEQ ID NO:39.

[1052] Item 597. A method as described in Item 594, wherein the at least one neoantigen comprises an amino acid sequence of any one of SEQ ID NOs:46-49.

[1053] Item 598. A method as described in Item 593, wherein the at least one new antigen comprises the amino acid sequence of any one of SEQ ID NOs: 66-93, or an antigenic portion of any one of SEQ ID NOs: 66-93.

[1054] Item 599. A method as described in Item 598, wherein the at least one new antigen comprises the amino acid sequence of SEQ ID NO:66, or the antigenic portion of SEQ ID NO:66.

[1055] Item 600. A method as described in Item 598, wherein the at least one new antigen comprises the amino acid sequence of any one of SEQ ID NOs:74-77, or an antigenic portion of any one of SEQ ID NOs:74-77.

[1056] Item 601. A method as described in any of Items 593 to 600, wherein the length of the at least one neoantigen and / or antigen portion is in the range of about 10 to about 50, about 10 to about 35, about 15 to about 25, or about 10 to about 20 amino acids.

[1057] Item 602. The method of any one of Items 593 to 601, wherein the at least one neoantigen and / or antigen portion is linked to the pharmaceutically acceptable carrier.

[1058] Item 603. A method as described in any one of Items 593 to 602, wherein the pharmaceutically acceptable carrier is selected from a peptide, serum albumin, keyhole limpet hemocyanin, an immunoglobulin, thyroglobulin, ovalbumin, a toxoid or an attenuated toxoid derivative, a cytokine and a chemokine.

[1059] Item 604. A method of treating a subject having or suspected of having a neoplastic disorder, the method comprising:

[1060] (a) administering to the subject an effective amount of a splicing regulator, the antibody-drug conjugate of any one of items 1 to 193, or the composition of any one of items 194 to 197;

[1061] (b) detecting one or more neoantigens in the subject after administration of the splicing modulator, antibody-drug conjugate, or composition;

[1062] (c) comparing the one or more neoantigens to a panel of universal neoantigens; and

[1063] (d) administering to the subject a universal neoantigen vaccine comprising at least one universal neoantigen present in the subject.

[1064] Item 605. The method of Item 604, wherein the universal neoantigen vaccine is administered alone or in combination with at least one additional therapy.

[1065] Item 606. The method of Item 605, 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.

[1066] Item 607. The method of Item 605 or Item 606, wherein the at least one additional therapy comprises repeated administration of the splicing regulator, antibody-drug conjugate, or composition.

[1067] Item 608. The method of Item 607, wherein repeated administration of the splicing regulator, antibody-drug conjugate, or composition is initiated prior to administration of the universal neoantigen vaccine.

[1068] Item 609. The method of Item 607, wherein repetition of the splicing regulator, antibody-drug conjugate, or composition is initiated after administration of the universal neoantigen vaccine.

[1069] Item 610. The method of Item 607, wherein repeated administration of the splicing regulator, antibody-drug conjugate, or composition is initiated simultaneously with administration of the universal neoantigen vaccine.

[1070] Item 611. The method of any one of Items 607 to 610, wherein the amount of the splicing regulator, antibody-drug conjugate, or composition used for repeated administration is reduced compared to the amount used for initial administration.

[1071] Item 612. The method of any one of Items 607 to 611, wherein the amount of the splicing regulator, antibody-drug conjugate, or composition for repeated administration is reduced compared to a standard dose of the splicing regulator, antibody-drug conjugate, or composition.

[1072] Item 613. The method of any one of Items 607 to 612, wherein the amount of the splicing regulator, 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 splicing regulator, antibody-drug conjugate, or composition.

[1073] Item 614. The method of any one of Items 605 to 613, wherein the at least one additional therapy comprises administration of a checkpoint inhibitor.

[1074] Item 615. The method of Item 614, wherein administration of the checkpoint inhibitor is initiated prior to administration of the universal neoantigen vaccine and / or repeated administration of the splicing regulator, antibody-drug conjugate, or composition.

[1075] Item 616. The method of Item 614, wherein administration of the checkpoint inhibitor is initiated after administration of the universal neoantigen vaccine and / or repetition of the splicing regulator, antibody-drug conjugate, or composition.

[1076] Item 617. The method of Item 614, wherein administration of the checkpoint inhibitor is initiated simultaneously with administration of the universal neoantigen vaccine and / or repeated administration of the splicing regulator, antibody-drug conjugate, or composition.

[1077] Item 618. The method of any one of Items 614 to 617, wherein after the initial administration, the checkpoint inhibitor is repeated at least once.

[1078] Item 619. The method of Item 618, wherein the amount of the checkpoint inhibitor for repeated administration is reduced compared to the amount for initial administration.

[1079] Item 620. The method of Item 618 or Item 619, wherein the amount of the checkpoint inhibitor for repeated administration is reduced compared to a standard dose of the checkpoint inhibitor.

[1080] Item 621. The method of any one of Items 618 to 620, 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.

[1081] Item 622. The method of any one of Items 614 to 621, wherein the subject is intolerant, unresponsive, or poorly responsive to the checkpoint inhibitor when administered alone.

[1082] Item 623. A method as described in any one of Items 614 to 622, wherein the checkpoint inhibitor targets CTLA4, PD1, PDL1, OX40, CD40, GITR, LAG3, TIM3 and / or KIR.

[1083] Item 624. The method of any one of Items 614 to 623, wherein the checkpoint inhibitor targets CTLA4, OX40, CD40 and / or GITR.

[1084] Item 625. A method as described in any one of Items 614 to 624, wherein the checkpoint inhibitor comprises a cytotoxic T lymphocyte-associated antigen 4 pathway (CTLA4) inhibitor.

[1085] Item 626. The method of Item 625, wherein the CTLA4 inhibitor is an anti-CTLA4 antibody.

[1086] Item 627. The method of Item 626, wherein the anti-CTLA4 antibody is ipilimumab.

[1087] Item 628. The method of any one of Items 614 to 624, wherein the checkpoint inhibitor comprises a programmed death-1 pathway (PD1) inhibitor.

[1088] Item 629. The method of Item 628, wherein the PD1 inhibitor is an anti-PD1 antibody.

[1089] Item 630. The method of Item 629, wherein the anti-PD1 antibody is nivolumab.

[1090] Item 631. The method of Item 628, wherein the PD1 inhibitor is an anti-PDL1 antibody.

[1091] Item 632. The method of Item 631, wherein the anti-PDL1 antibody is atezolizumab.

[1092] Item 633. A method as described in any one of Items 614 to 624, wherein the checkpoint inhibitor comprises a CTLA4 inhibitor and a PD1 inhibitor.

[1093] Item 634. The method of Item 633, wherein the CTLA4 inhibitor is an anti-CTLA4 antibody.

[1094] Item 635. The method of Item 634, wherein the anti-CTLA4 antibody is ipilimumab.

[1095] Item 636. The method of Item 633, wherein the PD1 inhibitor is an anti-PD1 antibody.

[1096] Item 637. The method of Item 636, wherein the anti-PD1 antibody is nivolumab.

[1097] Item 638. The method of Item 633, wherein the PD1 inhibitor is an anti-PDL1 antibody.

[1098] Item 639. The method of Item 638, wherein the anti-PDL1 antibody is atezolizumab.

[1099] Item 640. The method of any one of Items 604 to 639, wherein the universal neoantigen vaccine comprises at least one neoantigenic peptide.

[1100] Item 641. A method as described in Item 640, wherein the length of the at least one neoantigenic peptide is in the range of about 10 to about 50 or about 10 to about 35 amino acids.

[1101] Item 642. The method of Item 640 or Item 641, wherein the at least one neoantigenic peptide has a length ranging from about 15 to about 25 amino acids.

[1102] Item 643. The method of any one of Items 640 to 642, wherein the at least one neoantigenic peptide comprises one or more than one universal neoantigenic sequence.

[1103] Item 644. A method as described in Item 643, wherein the universal neoantigen sequence comprises the amino acid sequence of any one of SEQ ID NO:37-65.

[1104] Item 645. A method as described in Item 644, wherein the universal neoantigen sequence comprises the amino acid sequence of SEQ ID NO:37.

[1105] Item 646. A method as described in Item 644, wherein the universal neoantigen sequence comprises the amino acid sequence of SEQ ID NO:39.

[1106] Item 647. A method as described in Item 644, wherein the universal neoantigen sequence comprises the amino acid sequence of any one of SEQ ID NOs:46-49.

[1107] Item 648. A method as described in Item 643, wherein the universal neoantigen sequence comprises the amino acid sequence of any one of SEQ ID NOs: 66-93, or the antigenic portion of any one of SEQ ID NOs: 66-93.

[1108] Item 649. A method as described in Item 648, wherein the universal neoantigen sequence comprises the amino acid sequence of SEQ ID NO:66, or the antigenic portion of SEQ ID NO:66.

[1109] Item 650. A method as described in Item 648, wherein the universal neoantigen sequence comprises the amino acid sequence of any one of SEQ ID NOs:74-77, or the antigenic portion of any one of SEQ ID NOs:74-77.

[1110] Item 651. A method as described in any of Items 643 to 650, wherein the length of the universal neoantigen sequence and / or antigen portion is in the range of about 10 to about 50, about 10 to about 35, about 15 to about 25, or about 10 to about 20 amino acids.

[1111] Item 652. A method as described in any of Items 643 to 651, wherein the universal neoantigen sequence and / or antigen portion 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 subjects in a population of subjects suffering from the neoplastic disorder.

[1112] Item 653. A method as described in any of Items 643 to 652, wherein the universal neoantigen sequence and / or antigen portion 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 suffering from the neoplastic disorder.

[1113] Item 654. The method of any one of Items 604 to 639, wherein the universal neoantigen vaccine comprises at least one neoantigen peptide and a pharmaceutically acceptable carrier.

[1114] Item 655. The method of Item 654, wherein the at least one neoantigenic peptide is linked to the pharmaceutically acceptable carrier.

[1115] Item 656. The method of Item 654 or Item 655, wherein the pharmaceutically acceptable carrier is selected from a peptide, serum albumin, keyhole limpet hemocyanin, an immunoglobulin, thyroglobulin, ovalbumin, a toxoid or an attenuated toxoid derivative, a cytokine and a chemokine.

[1116] Item 657. The method of any one of Items 654 to 656, wherein the neoantigenic peptide and the pharmaceutically acceptable carrier are covalently linked via a linker.

[1117] Item 658. The method of any one of Items 654 to 656, wherein the neoantigenic peptide and the pharmaceutically acceptable carrier are expressed as a fusion protein.

[1118] Item 659. The method of any one of Items 604 to 639, wherein the universal neoantigen vaccine comprises at least one neoantigen peptide and a pharmaceutically acceptable diluent.

[1119] Item 660. The method of any one of Items 604 to 639, wherein the universal neoantigen vaccine comprises at least one neoantigen peptide and a pharmaceutically acceptable adjuvant.

[1120] Item 661. The method of any one of Items 604 to 639, wherein the universal neoantigen vaccine comprises at least one neoantigen mRNA.

[1121] Item 662. A method as described in Item 661, wherein the at least one neoantigen mRNA encodes one or more universal neoantigen sequences.

[1122] Item 663. A method as described in Item 662, wherein the universal neoantigen sequence comprises the amino acid sequence of any one of SEQ ID NO:37-65.

[1123] Item 664. A method as described in Item 663, wherein the universal neoantigen sequence comprises the amino acid sequence of SEQ ID NO:37.

[1124] Item 665. A method as described in Item 663, wherein the universal neoantigen sequence comprises the amino acid sequence of SEQ ID NO:39.

[1125] Item 666. A method as described in Item 663, wherein the universal neoantigen sequence comprises the amino acid sequence of any one of SEQ ID NOs:46-49.

[1126] Item 667. A method as described in Item 662, wherein the universal neoantigen sequence comprises the amino acid sequence of any one of SEQ ID NOs: 66-93, or the antigenic portion of any one of SEQ ID NOs: 66-93.

[1127] Item 668. A method as described in Item 667, wherein the universal neoantigen sequence comprises the amino acid sequence of SEQ ID NO:66, or the antigenic portion of SEQ ID NO:66.

[1128] Item 669. A method as described in Item 667, wherein the universal neoantigen sequence comprises the amino acid sequence of any one of SEQ ID NOs:74-77, or the antigenic portion of any one of SEQ ID NOs:74-77.

[1129] Item 670. A method as described in any of Items 662 to 669, wherein the length of the universal neoantigen sequence and / or antigen portion is in the range of about 10 to about 50, about 10 to about 35, about 15 to about 25, or about 10 to about 20 amino acids.

[1130] Item 671. A method as described in any of Items 662 to 670, wherein the universal neoantigen sequence and / or antigen portion 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 subjects in a population of subjects suffering from the neoplastic disorder.

[1131] Item 672. A method as described in any of Items 662 to 671, wherein the universal neoantigen sequence and / or antigen portion 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 suffering from the neoplastic disorder.

[1132] Item 673. The method of any one of Items 604 to 639, wherein the universal neoantigen vaccine comprises at least one neoantigen mRNA and a pharmaceutically acceptable carrier.

[1133] Item 674. The method of Item 673, wherein the at least one neoantigen mRNA is linked to the pharmaceutically acceptable carrier.

[1134] Item 675. The method of Item 673 or Item 674, wherein the pharmaceutically acceptable carrier is selected from a peptide, serum albumin, keyhole limpet hemocyanin, an immunoglobulin, thyroglobulin, ovalbumin, a toxoid or an attenuated toxoid derivative, a cytokine and a chemokine.

[1135] Item 676. The method of any one of Items 604 to 639, wherein the universal neoantigen vaccine comprises at least one neoantigen mRNA and a pharmaceutically acceptable diluent.

[1136] Item 677. The method of any one of Items 604 to 639, wherein the universal neoantigen vaccine comprises at least one neoantigen mRNA and a pharmaceutically acceptable adjuvant.

[1137] Item 678. A method as described in any one of Items 661 to 677, wherein the neoantigen mRNA is encapsulated by an encapsulating agent.

[1138] Item 679. The method of Item 678, wherein the encapsulating agent is a liposome.

[1139] Item 680. The method of Item 678, wherein the encapsulating agent is a nanoparticle.

[1140] Item 681. The method of any one of Items 604 to 680, wherein the subject has a non-synonymous mutation burden of approximately 150 mutations or fewer.

[1141] Item 682. The method of any one of Items 604 to 681, wherein the subject has a non-synonymous mutation burden of approximately 100 mutations or fewer.

[1142] Item 683. The method of any one of Items 604 to 682, wherein the subject has a non-synonymous mutation burden of approximately 50 mutations or fewer.

[1143] Item 684. The method of any one of Items 604 to 683, wherein the neoplastic disorder is a hematological malignancy or a solid tumor.

[1144] Item 685. The method of Item 684, wherein the hematological malignancy is selected from B-cell malignancies, leukemias, lymphomas, and myelomas.

[1145] Item 686. The method of Item 684 or Item 685, wherein the hematological malignancy is selected from acute myeloid leukemia and multiple myeloma.

[1146] Item 687. The method of Item 684, wherein the solid tumor is selected from breast cancer, gastric cancer, prostate cancer, ovarian cancer, lung cancer, uterine cancer, salivary duct cancer, melanoma, colon cancer, cervical cancer, pancreatic cancer, renal cancer, colorectal cancer and esophageal cancer.

[1147] Item 688. The method of any one of Items 303 to 687, wherein the antibody-drug conjugate comprises an antibody-drug conjugate having Formula (I):

[1148] Ab-(LD) p (I)

[1149] in

[1150] Ab is an antibody or antigen-binding fragment that targets neoplastic cells;

[1151] D is D2, D1, D4, D12 or D15;

[1152] L is a linker that covalently links Ab to D; and

[1153] p is an integer from 1 to 15.

[1154] Item 689. The method of Item 688, wherein the antibody or antigen-binding fragment targets cells expressing HER2.

[1155] Item 690. The method of Item 689, wherein the antibody or antigen-binding fragment is an anti-HER2 antibody or antigen-binding fragment.

[1156] Item 691. A method as described in Item 689 or Item 690, wherein the antibody or antigen-binding fragment comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) comprising 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) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2) and SEQID NO: 6 (LCDR3).

[1157] Item 692. The method of any one of Items 689 to 691, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 19 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 20.

[1158] Item 693. The method of Item 688, wherein the antibody or antigen-binding fragment targets cells expressing CD138.

[1159] Item 694. The method of Item 693, wherein the antibody or antigen-binding fragment is an anti-CD138 antibody or antigen-binding fragment.

[1160] Item 695. A method as described in Item 693 or Item 694, wherein the antibody or antigen-binding fragment comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) comprising the amino acid sequence of 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) comprising the amino acid sequence of SEQ ID NO: 10 (LCDR1), SEQ ID NO: 11 (LCDR2) and SEQ ID NO: 12 (LCDR3).

[1161] Item 696. A method as described in any one of Items 693 to 695, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 21 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 22.

[1162] Item 697. The method of Item 688, wherein the antibody or antigen-binding fragment targets cells expressing EPHA2.

[1163] Item 698. The method of Item 697, wherein the antibody or antigen-binding fragment is an anti-EPHA2 antibody or antigen-binding fragment.

[1164] Item 699. A method as described in Item 697 or Item 698, wherein the antibody or antigen-binding fragment comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) comprising the amino acid sequence of 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) comprising the amino acid sequence of SEQ ID NO: 16 (LCDR1), SEQ ID NO: 17 (LCDR2) and SEQ ID NO: 18 (LCDR3).

[1165] Item 700. The method of any one of Items 697 to 699, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 23 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 24.

[1166] Item 701. The method of any one of Items 688 to 700, wherein the linker is a cleavable linker.

[1167] Item 702. The method of Item 701, wherein the cleavable linker comprises MC-Val-Cit-pABC.

[1168] Item 703. The method of Item 701, wherein the cleavable linker comprises MC-Val-Ala-pABC.

[1169] Item 704. The method of Item 701, wherein the cleavable linker comprises MC-Val-Ala-pAB.

[1170] Item 705. The method of any one of Items 688 to 700, wherein the linker is a non-cleavable linker.

[1171] Item 706. The method of Item 705, wherein the non-cleavable linker comprises Mal-Hex.

[1172] Item 707. The method of Item 705, wherein the non-cleavable linker comprises Mal-Et.

[1173] Item 708. The method of Item 705, wherein the non-cleavable linker comprises Mal-Et-O-Et.

[1174] Item 709. The method of any one of Items 688 to 708, wherein the splicing regulator comprises D2:

[1175]

[1176] Item 710. The method of Item 709, wherein the splicing regulator comprises D2 and the linker comprises MC-Val-Ala-pAB.

[1177] Item 711. The method of any one of Items 688 to 708, wherein the splicing regulator comprises D1:

[1178]

[1179] Item 712. The method of Item 711, wherein the splicing regulator comprises D1 and the linker comprises MC-Val-Cit-pABC.

[1180] Item 713. The method of any one of Items 688 to 708, wherein the splicing regulator comprises a splicing regulator having Formula (II):

[1181] or a pharmaceutically acceptable salt thereof, wherein:

[1182] R 1is selected from the group consisting of absence, hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group, a -OC(=O)-(C1-C6 alkyl) group, and -CD3;

[1183] R 3 is selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group and a -OC(=O)-(C1-C6 alkyl) group; and

[1184] R 4 、R 5 and R 8 are each independently selected from hydrogen, a hydroxyl group, an —O—(C 1 -C 6 alkyl) group, a —OC(═O)—(C 1 -C 6 alkyl) group, and a C 1 -C 6 alkyl group;

[1185] R 6 and R 7 are each independently selected from hydrogen, -OR 17 、-OC(=O)-R 17 、-OC(=O)-NR 15 R 16 , C1-C6 alkyl groups and -NR 15 R 16 ;

[1186] R 15 and R 16 are each independently selected from hydrogen, R 17 、-C(=O)-R 17 and -C(=O)-OR 17 ;

[1187] R 17 is selected from hydrogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a benzyl group and a C3-C8 heterocyclyl group; and

[1188] Z is selected from

[1189] where R 1 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 15 、R16 and R 17 Each is independently substituted by 0 to 3 groups independently selected from the following: halogen, hydroxyl group, C1-C6 alkyl group, -O-(C1-C6 alkyl) group, -NR 15 R 16 , a C3-C8 cycloalkyl group, a C1-C6 alkylhydroxyl group, a C1-C6 alkylalkoxy group, a benzyl group and a C3-C8 heterocyclyl group,

[1190] where R 6 and R 7 At least one of them is hydrogen.

[1191] Item 714. The method of any one of Items 688 to 708, wherein the splicing regulator comprises a splicing regulator having Formula (IV):

[1192] or a pharmaceutically acceptable salt thereof, wherein:

[1193] R 1 is selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group, a -OC(=O)-(C1-C6 alkyl) group and -CD3;

[1194] R 3 is selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group and a -OC(=O)-(C1-C6 alkyl) group; and

[1195] R 4 、R 5 and R 8 are each independently selected from hydrogen, a hydroxyl group, an —O—(C 1 -C 6 alkyl) group, a —OC(═O)—(C 1 -C 6 alkyl) group, and a C 1 -C 6 alkyl group;

[1196] R 6 and R 7 are each independently selected from hydrogen, -OR 17 、-OC(=O)-R 17 、-OC(=O)-NR 15 R 16 , C1-C6 alkyl groups and -NR 15 R 16 ;

[1197] R 15 and R 16 are each independently selected from hydrogen, R 17 、-C(=O)-R 17 and

[1198] -C(=O)-OR 17 ;and

[1199] R 17 is selected from hydrogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a benzyl group and a C3-C8 heterocyclyl group;

[1200] where R 1 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 15 、R 16 and R 17 Each is independently substituted by 0 to 3 groups independently selected from the following: halogen, hydroxyl group, C1-C6 alkyl group, -O-(C1-C6 alkyl) group, -NR 15 R 16 , a C3-C8 cycloalkyl group, a C1-C6 alkylhydroxyl group, a C1-C6 alkylalkoxy group, a benzyl group and a C3-C8 heterocyclyl group,

[1201] where R 6 and R 7 At least one of them is hydrogen.

[1202] Item 715. The method of any one of Items 688 to 708, wherein the splicing regulator comprises a splicing regulator having Formula (VI):

[1203] or a pharmaceutically acceptable salt thereof, wherein:

[1204] R 1 and R 9 Each is independently selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group, a -OC(=O)-(C1-C6 alkyl) group and -CD3;

[1205] R 3is selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group and a -OC(=O)-(C1-C6 alkyl) group;

[1206] R 4 、R 5 and R 8 are each independently selected from hydrogen, a hydroxyl group, an —O—(C 1 -C 6 alkyl) group, a —OC(═O)—(C 1 -C 6 alkyl) group, and a C 1 -C 6 alkyl group;

[1207] R 6 and R 7 are each independently selected from hydrogen, -OR 17 、-OC(=O)-R 17 、-OC(=O)-NR 15 R 16 , C1-C6 alkyl group, -NR 15 R 16 and joints;

[1208] R 10 is selected from hydrogen, a C1-C6 alkyl group, a -C(=O)-(C1-C6 alkyl) group and -CD3;

[1209] R 15 and R 16 are each independently selected from hydrogen, R 17 、-C(=O)-R 17 and -C(=O)-OR 17 ;

[1210] R 17 is selected from hydrogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a benzyl group and a C3-C8 heterocyclyl group; and

[1211] a is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[1212] where R 1 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 15 、R 16 and R 17Each is independently substituted by 0 to 3 groups independently selected from the following: halogen, hydroxyl group, C1-C6 alkyl group, -O-(C1-C6 alkyl) group, -NR 15 R 16 , a C3-C8 cycloalkyl group, a C1-C6 alkylhydroxyl group, a C1-C6 alkylalkoxy group, a benzyl group and a C3-C8 heterocyclyl group;

[1213] where R 6 and R 7 At least one of is hydrogen; and

[1214] where R 1 and R 9 Cannot exist at the same time.

[1215] Item 716. The method of any one of Items 688 to 708, wherein the splicing regulator comprises a splicing regulator having Formula (VIII):

[1216] or a pharmaceutically acceptable salt thereof, wherein:

[1217] R 1 is selected from the group consisting of absence, hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group, a -OC(=O)-(C1-C6 alkyl) group, and -CD3;

[1218] R 3 is selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkylalkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C1-C6 alkylhydroxyl group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group and a -OC(=O)-(C1-C6 alkyl) group;

[1219] R 4 is selected from hydrogen, a hydroxyl group, an —O—(C 1 -C 6 alkyl) group, a —OC(═O)—(C 1 -C 6 alkyl) group, and a C 1 -C 6 alkyl group; and

[1220] R 10 selected from 3 to 10 membered carbocyclic rings and 3 to 10 membered heterocyclic rings, each of which is surrounded by 0 to 3 R a Substitute, where each R a independently selected from halogen, C1-C6 alkyl group, -O-(C1-C6)alkyl group, C1-C6 alkylalkoxy group, C1-C6 alkylhydroxyl group, -S(=O) w-(4- to 7-membered heterocyclic ring), 4- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring;

[1221] R 15 and R 16 are each independently selected from hydrogen, R 17 、-C(=O)-R 17 and -C(=O)-OR 17 ;and

[1222] R 17 is selected from hydrogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a benzyl group and a C3-C8 heterocyclyl group;

[1223] where R 1 、R 3 、R 4 、R 10 、R 15 、R 16 and R 17 Each is independently substituted by 0 to 3 groups independently selected from the following: halogen, hydroxyl group, C1-C6 alkyl group, -O-(C1-C6 alkyl) group, -NR 15 R 16 , a C3-C8 cycloalkyl group, a C1-C6 alkylhydroxy group, a C1-C6 alkylalkoxy group, a benzyl group, and a C3-C8 heterocyclyl group; and

[1224] Each R a is independently substituted with 0 to 3 groups independently selected from the group consisting of halogen, hydroxyl, -NR 15 R 16 , C1-C6 alkyl group, -(C=O)-(C1-C6 alkyl) group, -(C=O)-(C1-C6 alkyl)-(C3-C 10 heterocyclyl) group, -S(=O) w -(C3-C8 heterocyclyl group) and C1-C6 alkylcarboxylic acid group, each of which is substituted by 0, 1 or 2 groups independently selected from the group consisting of halogen, hydroxyl group, -NR 15 R 16 and a C1-C3 alkyl group; and

[1225] w is 0, 1, or 2.

[1226] Item 717. The method of any one of Items 688 to 708, wherein the splicing regulator comprises a regulator of the SF3b complex.

[1227] Item 718. The method of Item 717, wherein the splicing regulator comprises pradienolide or a pradienolide derivative.

[1228] Item 719. The method of Item 717 or Item 718, wherein the splicing regulator comprises pradienolide D or a pradienolide D derivative.

[1229] Item 720. A method as described in Item 719, wherein the pradienolide D or derivative comprises D2, D1, D4, D8, D10, D11 (E7107), D20, D21, D22, D12 or D25.

[1230] Item 721. The method of Item 719 or Item 720, wherein the pradienolide D or derivative comprises D2.

[1231] Item 722. The method of Item 719 or Item 720, wherein the pradienolide D or derivative comprises D1.

[1232] Item 723. The method of Item 719 or Item 720, wherein the pradienolide D or derivative is a zwitterionic pradienolide D or derivative.

[1233] Item 724. The method of Item 723, wherein the zwitterionic pradienolide D or derivative comprises D22 or D25.

[1234] Item 725. The method of Item 717 or Item 718, wherein the splicing regulator comprises pradienolide B or a pradienolide B derivative.

[1235] Item 726. The method of Item 725, wherein the pradienolide B or derivative comprises D9, D18, D19 or D13.

[1236] Item 727. The method of Item 717 or Item 718, wherein the splicing regulator comprises an aryl pramide diene lactone.

[1237] Item 728. The method of Item 727, wherein the aryl pradienolide comprises D15, D14, D16, D17, D26 or D33.

[1238] Item 729. The method of Item 727 or Item 728, wherein the aryl pramide diene lactone is a zwitterionic aryl pramide diene lactone.

[1239] Item 730. The method of Item 729, wherein the zwitterionic aryl pramide diene lactone comprises D33.

[1240] Item 731. The method of any one of Items 688 to 708, wherein the splicing regulator comprises D4, D12, D15, D8, D9, D10, D13, D18, D19, D20, D21, D22, D25 or D33.

[1241] Item 732. The method of any one of Items 688 to 731, wherein p is 2 to 8.

[1242] Item 733. The method of any one of Items 688 to 732, wherein p is 4 to 8.

[1243] Item 734. The method of any one of Items 688 to 733, wherein p is 4 or 8.

[1244] Item 735. A neoantigen vaccine comprising at least one neoantigen peptide, wherein the at least one neoantigen peptide comprises a modified or novel neoantigen sequence induced by contacting neoplastic cells with an effective amount of a splicing regulator, an antibody-drug conjugate as described in any one of Items 1 to 193, or a composition as described in any one of Items 194 to 197.

[1245] Item 736. The neoantigen vaccine of Item 735, wherein the length of at least one neoantigen peptide ranges from about 10 to about 50 or about 10 to about 35 amino acids.

[1246] Item 737. The neoantigen vaccine of Item 735 or Item 736, wherein the at least one neoantigen peptide has a length ranging from about 15 to about 25 amino acids.

[1247] Item 738. The neoantigen vaccine of any one of Items 735 to 737, wherein the modified or novel neoantigen sequence comprises the amino acid sequence of any one of SEQ ID NOs: 37-65.

[1248] Item 739. The neoantigen vaccine of Item 738, wherein the modified or novel neoantigen sequence comprises the amino acid sequence of SEQ ID NO: 37.

[1249] Item 740. The neoantigen vaccine of Item 738, wherein the modified or novel neoantigen sequence comprises the amino acid sequence of SEQ ID NO: 39.

[1250] Item 741. The neoantigen vaccine of Item 738, wherein the modified or novel neoantigen sequence comprises the amino acid sequence of any one of SEQ ID NOs: 46-49.

[1251] Item 742. The neoantigen vaccine of any one of Items 735 to 737, wherein the modified or novel neoantigen sequence comprises the amino acid sequence of any one of SEQ ID NOs: 66-93, or the antigenic portion of any one of SEQ ID NOs: 66-93.

[1252] Item 743. The neoantigen vaccine of Item 742, wherein the modified or novel neoantigen sequence comprises the amino acid sequence of SEQ ID NO: 66, or the antigenic portion of SEQ ID NO: 66.

[1253] Item 744. The neoantigen vaccine of Item 742, wherein the modified or novel neoantigen sequence comprises the amino acid sequence of any one of SEQ ID NOs: 74-77, or the antigenic portion of any one of SEQ ID NOs: 74-77.

[1254] Item 745. A neoantigen vaccine as described in any of Items 735 to 744, wherein the length of the modified or novel neoantigen sequence and / or antigen portion is in the range of about 10 to about 50, about 10 to about 35, about 15 to about 25, or about 10 to about 20 amino acids.

[1255] Item 746. The neoantigen vaccine of any one of Items 735 to 745, further comprising a pharmaceutically acceptable carrier.

[1256] Item 747. The neoantigen vaccine of Item 746, wherein the at least one neoantigen peptide is linked to the pharmaceutically acceptable carrier.

[1257] Item 748. The neoantigen vaccine of Item 746 or Item 747, wherein the pharmaceutically acceptable carrier is selected from a peptide, serum albumin, keyhole limpet hemocyanin, an immunoglobulin, thyroglobulin, ovalbumin, a toxoid or an attenuated toxoid derivative, a cytokine and a chemokine.

[1258] Item 749. The neoantigen vaccine of any one of Items 746 to 748, wherein the neoantigen peptide and the pharmaceutically acceptable carrier are covalently linked via a linker.

[1259] Item 750. The neoantigen vaccine of any one of Items 746 to 748, wherein the neoantigen peptide and the pharmaceutically acceptable carrier are expressed as a fusion protein.

[1260] Item 751. The neoantigen vaccine of any one of Items 735 to 745, further comprising a pharmaceutically acceptable diluent.

[1261] Item 752. The neoantigen vaccine of any one of Items 735 to 745, further comprising a pharmaceutically acceptable adjuvant.

[1262] Item 753. The neoantigen vaccine of any one of Items 735 to 752, wherein the neoplastic cells are present in an in vitro cell culture.

[1263] Item 754. The neoantigen vaccine of Item 753, wherein the neoplastic cells are obtained from a subject.

[1264] Item 755. The neoantigen vaccine of any one of Items 735 to 752, wherein the neoplastic cells are present in the subject.

[1265] Item 756. A neoantigen vaccine comprising at least one neoantigen mRNA, wherein the at least one neoantigen mRNA encodes a modified or novel neoantigen sequence induced by contacting neoplastic cells with an effective amount of a splicing regulator, an antibody-drug conjugate as described in any one of Items 1 to 193, or a composition as described in any one of Items 194 to 197.

[1266] Item 757. The neoantigen vaccine of Item 756, wherein the modified or novel neoantigen sequence comprises the amino acid sequence of any one of SEQ ID NOs: 37-65.

[1267] Item 758. The neoantigen vaccine of Item 757, wherein the modified or novel neoantigen sequence comprises the amino acid sequence of SEQ ID NO: 37.

[1268] Item 759. The neoantigen vaccine of Item 757, wherein the modified or novel neoantigen sequence comprises the amino acid sequence of SEQ ID NO: 39.

[1269] Item 760. The neoantigen vaccine of Item 757, wherein the modified or novel neoantigen sequence comprises the amino acid sequence of any one of SEQ ID NOs: 46-49.

[1270] Item 761. The neoantigen vaccine of Item 756, wherein the modified or novel neoantigen sequence comprises the amino acid sequence of any one of SEQ ID NOs: 66-93, or the antigenic portion of any one of SEQ ID NOs: 66-93.

[1271] Item 762. The neoantigen vaccine of Item 761, wherein the modified or novel neoantigen sequence comprises the amino acid sequence of SEQ ID NO: 66, or the antigenic portion of SEQ ID NO: 66.

[1272] Item 763. The neoantigen vaccine of Item 761, wherein the modified or novel neoantigen sequence comprises the amino acid sequence of any one of SEQ ID NOs: 74-77, or the antigenic portion of any one of SEQ ID NOs: 74-77.

[1273] Item 764. A neoantigen vaccine as described in any of Items 756 to 763, wherein the length of the modified or novel neoantigen sequence and / or antigen portion is in the range of about 10 to about 50, about 10 to about 35, about 15 to about 25, or about 10 to about 20 amino acids.

[1274] Item 765. The neoantigen vaccine of any one of Items 756 to 764, further comprising a pharmaceutically acceptable carrier.

[1275] Item 766. The neoantigen vaccine of Item 765, wherein the at least one neoantigen mRNA is linked to the pharmaceutically acceptable carrier.

[1276] Item 767. A new antigen vaccine as described in Item 765 or Item 766, 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.

[1277] Item 768. The neoantigen vaccine of any one of Items 756 to 764, further comprising a pharmaceutically acceptable diluent.

[1278] Item 769. The neoantigen vaccine of any one of Items 756 to 764, further comprising a pharmaceutically acceptable adjuvant.

[1279] Item 770. The neoantigen vaccine of any one of Items 756 to 769, wherein the neoantigen mRNA is encapsulated by an encapsulating agent.

[1280] Item 771. The neoantigen vaccine of Item 770, wherein the encapsulating agent is a liposome.

[1281] Item 772. The neoantigen vaccine of Item 770, wherein the encapsulating agent is a nanoparticle.

[1282] Item 773. The neoantigen vaccine of any one of Items 756 to 772, wherein the neoplastic cells are present in an in vitro cell culture.

[1283] Item 774. The neoantigen vaccine of Item 773, wherein the neoplastic cells are obtained from a subject.

[1284] Item 775. The neoantigen vaccine of any one of Items 756 to 772, wherein the neoplastic cells are present in the subject.

[1285] Item 776. The antibody-drug conjugate of any one of Items 1 to 7, wherein the antibody or antigen-binding fragment targets cells expressing MSLN.

[1286] Item 777. The antibody-drug conjugate of Item 776, wherein the antibody or antigen-binding fragment is an anti-MSLN antibody or antigen-binding fragment.

[1287] Item 778. The antibody-drug conjugate of any one of Items 1 to 7, wherein the antibody or antigen-binding fragment targets cells expressing FOLH1.

[1288] Item 779. The antibody-drug conjugate of Item 778, wherein the antibody or antigen-binding fragment is an anti-FOLH1 antibody or antigen-binding fragment.

[1289] Item 780. The antibody-drug conjugate of any one of Items 1 to 7, wherein the antibody or antigen-binding fragment targets cells expressing CDH6.

[1290] Item 781. The antibody-drug conjugate of Item 780, wherein the antibody or antigen-binding fragment is an anti-CDH6 antibody or antigen-binding fragment.

[1291] Item 782. The antibody-drug conjugate of any one of Items 1 to 7, wherein the antibody or antigen-binding fragment targets cells expressing CEACAM5.

[1292] Item 783. The antibody-drug conjugate of Item 782, wherein the antibody or antigen-binding fragment is an anti-CEACAM5 antibody or antigen-binding fragment.

[1293] Item 784. The antibody-drug conjugate of any one of Items 1 to 7, wherein the antibody or antigen-binding fragment targets cells expressing CFC1B.

[1294] Item 785. The antibody-drug conjugate of Item 784, wherein the antibody or antigen-binding fragment is an anti-CFC1B antibody or antigen-binding fragment.

[1295] Item 786. The antibody-drug conjugate of any one of Items 1 to 7, wherein the antibody or antigen-binding fragment targets cells expressing ENPP3.

[1296] Item 787. The antibody-drug conjugate of Item 786, wherein the antibody or antigen-binding fragment is an anti-ENPP3 antibody or antigen-binding fragment.

[1297] Item 788. The antibody-drug conjugate of any one of Items 1 to 7, wherein the antibody or antigen-binding fragment targets cells expressing FOLR1.

[1298] Item 789. The antibody-drug conjugate of Item 788, wherein the antibody or antigen-binding fragment is an anti-FOLR1 antibody or antigen-binding fragment.

[1299] Item 790. The antibody-drug conjugate of any one of Items 1 to 7, wherein the antibody or antigen-binding fragment targets cells expressing HAVCR1.

[1300] Item 791. The antibody-drug conjugate of Item 790, wherein the antibody or antigen-binding fragment is an anti-HAVCR1 antibody or antigen-binding fragment.

[1301] Item 792. The antibody-drug conjugate of any one of Items 1 to 7, wherein the antibody or antigen-binding fragment targets cells expressing KIT.

[1302] Item 793. The antibody-drug conjugate of Item 792, wherein the antibody or antigen-binding fragment is an anti-KIT antibody or antigen-binding fragment.

[1303] Item 794. The antibody-drug conjugate of any one of Items 1 to 7, wherein the antibody or antigen-binding fragment targets cells expressing MET.

[1304] Item 795. The antibody-drug conjugate of Item 794, wherein the antibody or antigen-binding fragment is an anti-MET antibody or antigen-binding fragment.

[1305] Item 796. The antibody-drug conjugate of any one of Items 1 to 7, wherein the antibody or antigen-binding fragment targets cells expressing MUC16.

[1306] Item 797. The antibody-drug conjugate of Item 796, wherein the antibody or antigen-binding fragment is an anti-MUC16 antibody or antigen-binding fragment.

[1307] Item 798. The antibody-drug conjugate of any one of Items 1 to 7, wherein the antibody or antigen-binding fragment targets cells expressing SLC39A6.

[1308] Item 799. The antibody-drug conjugate of Item 798, wherein the antibody or antigen-binding fragment is an anti-SLC39A6 antibody or antigen-binding fragment.

[1309] Item 800. The antibody-drug conjugate of any one of Items 1 to 7, wherein the antibody or antigen-binding fragment targets cells expressing SLC44A4.

[1310] Item 801. The antibody-drug conjugate of Item 800, wherein the antibody or antigen-binding fragment is an anti-SLC44A4 antibody or antigen-binding fragment.

[1311] Item 802. The antibody-drug conjugate of any one of Items 1 to 7, wherein the antibody or antigen-binding fragment targets cells expressing STEAP1.

[1312] Item 803. The antibody-drug conjugate of Item 802, wherein the antibody or antigen-binding fragment is an anti-STEAP1 antibody or antigen-binding fragment.

[1313] Item 804. The antibody-drug conjugate of Item 29, wherein the amino acid unit comprises glutamine-valine-citrulline (Glu-Val-Cit).

[1314] Item 805. The antibody-drug conjugate of Item 29, wherein the amino acid unit comprises alanine-alanine-asparagine (Ala-Ala-Asn).

[1315] Item 806. The antibody-drug conjugate of Item 48 or Item 49, wherein the cleavable peptide portion or amino acid unit comprises Glu-Val-Cit.

[1316] Item 807. The antibody-drug conjugate of Item 48 or Item 49, wherein the cleavable peptide portion or amino acid unit comprises Ala-Ala-Asn.

[1317] Item 808. The antibody-drug conjugate of any one of Items 55 to 58, wherein the linker comprises MC-Glu-Val-Cit.

[1318] Item 809. The antibody-drug conjugate of any one of Items 55 to 58, wherein the linker comprises MC-Ala-Ala-Asn.

[1319] Item 810. The antibody-drug conjugate of any one of Items 67 to 71, wherein the linker comprises Glu-Val-Cit-pABC.

[1320] Item 811. The antibody-drug conjugate of any one of Items 67 to 71, wherein the linker comprises Ala-Ala-Asn-pABC.

[1321] Item 812. The antibody-drug conjugate of any one of Items 74 to 78, wherein the linker comprises Glu-Val-Cit-pAB.

[1322] Item 813. The antibody-drug conjugate of any one of Items 74 to 78, wherein the linker comprises Ala-Ala-Asn-pAB.

[1323] Item 814. The antibody-drug conjugate of Item 117 or Item 118, wherein the pradienolide D or derivative comprises D4.

[1324] Item 815. The antibody-drug conjugate of Item 117 or Item 118, wherein the pradienolide D or derivative comprises D12.

[1325] Item 816. The antibody-drug conjugate of Item 125 or Item 126, wherein the aryl pramide diene lactone comprises D15.

[1326] Item 817. The antibody-drug conjugate of any one of Items 1 to 106, wherein the splicing regulator comprises D4:

[1327]

[1328] Item 818. The antibody-drug conjugate of Item 817, wherein the splicing regulator comprises D4 and the linker comprises MC-Val-Cit-pABC.

[1329] Item 819. The antibody-drug conjugate of Item 817, wherein the splicing regulator comprises D4 and the linker comprises MC-β-glucuronide.

[1330] Item 820. The antibody-drug conjugate of any one of Items 1 to 106, wherein the splicing regulator comprises D12:

[1331]

[1332] Item 821. The antibody-drug conjugate of 820, wherein the splicing regulator comprises D12 and the linker comprises MC-Val-Cit-pABC.

[1333] Item 822. The antibody-drug conjugate of Item 820, wherein the splicing regulator comprises D12 and the linker comprises MC-β-glucuronide.

[1334] Item 823. The antibody-drug conjugate of any one of Items 1 to 106, wherein the splicing regulator comprises D15:

[1335]

[1336] Item 824. The antibody-drug conjugate of 823, wherein the splicing regulator comprises D15 and the linker comprises MC-Val-Ala-pAB.

[1337] Item 825. An antibody-drug conjugate as described in Item 137, wherein the antibody or antigen-binding fragment targets cells expressing HER2, CD138, EPHA2, MSLN, FOLH1, CDH6, CEACAM5, CFC1B, ENPP3, FOLR1, HAVCR1, KIT, MET, MUC16, SLC39A6, SLC44A4 and / or STEAP1.

[1338] Item 826. An antibody-drug conjugate as described in Item 156, wherein the antibody or antigen-binding fragment targets cells expressing HER2, CD138, EPHA2, MSLN, FOLH1, CDH6, CEACAM5, CFC1B, ENPP3, FOLR1, HAVCR1, KIT, MET, MUC16, SLC39A6, SLC44A4 and / or STEAP1.

[1339] Item 827. An antibody-drug conjugate having formula (I),

[1340] Ab-(LD) p (I)

[1341] in

[1342] Ab is an antibody or antigen-binding fragment that targets neoplastic cells;

[1343] D is D4;

[1344] L is a linker that covalently links Ab to D; and

[1345] p is an integer from 1 to 15.

[1346] Item 828. The antibody-drug conjugate of Item 827, wherein the antibody or antigen-binding fragment targets cells expressing HER2.

[1347] Item 829. The antibody-drug conjugate of Item 828, wherein the antibody or antigen-binding fragment is an anti-HER2 antibody or antigen-binding fragment.

[1348] Item 830. An antibody-drug conjugate as described in Item 828 or Item 829, wherein the antibody or antigen-binding fragment comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) comprising 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) comprising the amino acid sequences of SEQ ID NO:4 (LCDR1), SEQ ID NO:5 (LCDR2) and SEQ ID NO:6 (LCDR3).

[1349] Item 831. An antibody-drug conjugate as described in any one of Items 828 to 830, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 19 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 20.

[1350] Item 832. The antibody-drug conjugate of any one of Items 828 to 831, wherein the antibody or antigen-binding fragment comprises a human IgG1 heavy chain constant region.

[1351] Item 833. The antibody-drug conjugate of any one of Items 828 to 832, wherein the antibody or antigen-binding fragment comprises a human Igκ light chain constant region.

[1352] Item 834. An antibody-drug conjugate as described in Item 827, wherein the antibody or antigen-binding fragment targets cells expressing HER2, CD138, EPHA2, MSLN, FOLH1, CDH6, CEACAM5, CFC1B, ENPP3, FOLR1, HAVCR1, KIT, MET, MUC16, SLC39A6, SLC44A4 and / or STEAP1.

[1353] Item 835. An antibody-drug conjugate having formula (I),

[1354] Ab-(LD) p (I)

[1355] in

[1356] Ab is an antibody or antigen-binding fragment that targets neoplastic cells;

[1357] D is D12;

[1358] L is a linker that covalently links Ab to D; and

[1359] p is an integer from 1 to 15.

[1360] Item 836. An antibody-drug conjugate as described in Item 835, wherein the antibody or antigen-binding fragment targets cells expressing HER2.

[1361] Item 837. An antibody-drug conjugate as described in Item 836, wherein the antibody or antigen-binding fragment is an anti-HER2 antibody or antigen-binding fragment.

[1362] Item 838. An antibody-drug conjugate as described in Item 836 or Item 837, wherein the antibody or antigen-binding fragment comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) comprising 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) comprising the amino acid sequences of SEQ ID NO:4 (LCDR1), SEQ ID NO:5 (LCDR2) and SEQ ID NO:6 (LCDR3).

[1363] Item 839. An antibody-drug conjugate as described in any one of Items 836 to 838, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 19 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 20.

[1364] Item 840. The antibody-drug conjugate of any one of Items 836 to 839, wherein the antibody or antigen-binding fragment comprises a human IgG1 heavy chain constant region.

[1365] Item 841. The antibody-drug conjugate of any one of Items 836 to 840, wherein the antibody or antigen-binding fragment comprises a human Igκ light chain constant region.

[1366] Item 842. An antibody-drug conjugate as described in Item 835, wherein the antibody or antigen-binding fragment targets cells expressing HER2, CD138, EPHA2, MSLN, FOLH1, CDH6, CEACAM5, CFC1B, ENPP3, FOLR1, HAVCR1, KIT, MET, MUC16, SLC39A6, SLC44A4 and / or STEAP1.

[1367] Item 843. An antibody-drug conjugate having formula (I),

[1368] Ab-(LD) p (I)

[1369] in

[1370] Ab is an antibody or antigen-binding fragment that targets neoplastic cells;

[1371] D is D15;

[1372] L is a linker that covalently links Ab to D; and

[1373] p is an integer from 1 to 15.

[1374] Item 844. An antibody-drug conjugate as described in Item 843, wherein the antibody or antigen-binding fragment targets cells expressing HER2.

[1375] Item 845. The antibody-drug conjugate of Item 844, wherein the antibody or antigen-binding fragment is an anti-HER2 antibody or antigen-binding fragment.

[1376] Item 846. An antibody-drug conjugate as described in Item 844 or Item 845, wherein the antibody or antigen-binding fragment comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) comprising 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) comprising the amino acid sequences of SEQ ID NO:4 (LCDR1), SEQ ID NO:5 (LCDR2) and SEQ ID NO:6 (LCDR3).

[1377] Item 847. An antibody-drug conjugate as described in any one of Items 844 to 846, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 19 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 20.

[1378] Item 848. The antibody-drug conjugate of any one of Items 844 to 847, wherein the antibody or antigen-binding fragment comprises a human IgG1 heavy chain constant region.

[1379] Item 849. The antibody-drug conjugate of any one of Items 844 to 848, wherein the antibody or antigen-binding fragment comprises a human Igκ light chain constant region.

[1380] Item 850. An antibody-drug conjugate as described in Item 843, wherein the antibody or antigen-binding fragment targets cells expressing HER2, CD138, EPHA2, MSLN, FOLH1, CDH6, CEACAM5, CFC1B, ENPP3, FOLR1, HAVCR1, KIT, MET, MUC16, SLC39A6, SLC44A4 and / or STEAP1.

[1381] Item 851. The antibody-drug conjugate of any one of Items 827 to 850, wherein the linker is a cleavable linker.

[1382] Item 852. The antibody-drug conjugate of Item 851, wherein the cleavable linker comprises MC-Val-Cit-pABC.

[1383] Item 853. The antibody-drug conjugate of Item 851, wherein the cleavable linker comprises MC-Val-Ala-pABC.

[1384] Item 854. The antibody-drug conjugate of Item 851, wherein the cleavable linker comprises MC-Val-Ala-pAB.

[1385] Item 855. The antibody-drug conjugate of Item 851, wherein the cleavable linker comprises MC-Glu-Val-Cit-pABC.

[1386] Item 856. The antibody-drug conjugate of Item 851, wherein the cleavable linker comprises MC-Ala-Ala-Asn-pABC.

[1387] Item 857. The antibody-drug conjugate of Item 851, wherein the cleavable linker comprises MC-β-glucuronide.

[1388] Item 858. The antibody-drug conjugate of any one of Items 827 to 850, wherein the linker is a non-cleavable linker.

[1389] Item 859. The antibody-drug conjugate of Item 858, wherein the non-cleavable linker comprises Mal-Hex.

[1390] Item 860. The antibody-drug conjugate of Item 858, wherein the non-cleavable linker comprises Mal-Et.

[1391] Item 861. The antibody-drug conjugate of Item 858, wherein the non-cleavable linker comprises Mal-Et-O-Et.

[1392] Item 862. The antibody-drug conjugate of any one of Items 827 to 861, wherein p is 1 to 10.

[1393] Item 863. The antibody-drug conjugate of any one of Items 827 to 862, wherein p is 2 to 8.

[1394] Item 864. The antibody-drug conjugate of any one of Items 827 to 863, wherein p is 4 to 8.

[1395] Item 865. The antibody-drug conjugate of any one of Items 827 to 864, wherein p is 4.

[1396] Item 866. The antibody-drug conjugate of any one of Items 827 to 864, wherein p is 8.

[1397] Item 867. The antibody-drug conjugate of Item 181, wherein the cleavable linker comprises MC-Glu-Val-Cit-pABC.

[1398] Item 868. The antibody-drug conjugate of Item 181, wherein the cleavable linker comprises MC-Ala-Ala-Asn-pABC.

[1399] Item 869. A composition comprising multiple copies of the antibody-drug conjugate of any one of Items 776 to 868, wherein the average p of the antibody-drug conjugate in the composition is about 3.5 to about 5.5.

[1400] Item 870. A composition comprising multiple copies of the antibody-drug conjugate of any one of Items 776 to 868, wherein the average p of the antibody-drug conjugate in the composition is about 7 to about 9.

[1401] Item 871. 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 an antibody-drug conjugate as described in any one of Items 776 to 868 or a composition as described in Item 869 or Item 870.

[1402] Item 872. 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 an antibody-drug conjugate as described in any one of Items 776 to 868 or a composition as described in Item 869 or Item 870.

[1403] Item 873. A method for determining whether a subject having or suspected of having a neoplastic disorder will respond to treatment with an antibody-drug conjugate as described in any one of Items 776 to 868 or a composition as described in Item 869 or Item 870, the method comprising providing a biological sample from the subject and contacting the biological sample with the antibody-drug conjugate as described in any one of Items 776 to 868 or a composition as described in Item 869 or Item 870.

[1404] Item 874. The antibody-drug conjugate of any one of Items 776 to 868 or the composition of Item 869 or Item 870 for use in treating a neoplastic disorder.

[1405] Item 875. Use of an antibody-drug conjugate as described in any one of Items 776 to 868 or a composition as described in Item 869 or Item 870 for treating a neoplastic disorder.

[1406] Item 876. Use of the antibody-drug conjugate of any one of Items 776 to 868 or the composition of Item 869 or Item 870 in a method for the manufacture of a medicament for treating a neoplastic disorder.

[1407] Item 877. A pharmaceutical composition comprising the antibody-drug conjugate described in any one of Items 776 to 868 or the composition described in Item 869 or Item 870, and a pharmaceutically acceptable carrier.

[1408] Item 878. A method of producing an antibody-drug conjugate as described in any of Items 776 to 868, the method comprising reacting the antibody or antigen-binding fragment with a linker conjugated to a splicing regulator under conditions that allow conjugation.

[1409] Item 879. The method of any one of Items 303 to 687, wherein the antibody-drug conjugate comprises the antibody-drug conjugate of any one of Items 776 to 868.

[1410] Item 880. The method of Item 688, wherein the antibody or antigen-binding fragment targets cells expressing HER2, CD138, EPHA2, MSLN, FOLH1, CDH6, CEACAM5, CFC1B, ENPP3, FOLR1, HAVCR1, KIT, MET, MUC16, SLC39A6, SLC44A4 and / or STEAP1.

[1411] Item 881. The method of Item 701, wherein the cleavable linker comprises MC-Glu-Val-Cit-pABC.

[1412] Item 882. The method of Item 701, wherein the cleavable linker comprises MC-Ala-Ala-Asn-pABC.

[1413] Item 883. The method of Item 701, wherein the cleavable linker comprises MC-β-glucuronide.

[1414] Item 884. The method of any one of Items 688 to 708, wherein the splicing regulator comprises D4:

[1415]

[1416] Item 885. The method of Item 884, wherein the splicing regulator comprises D4 and the linker comprises MC-Val-Cit-pABC.

[1417] Item 886. The method of Item 884, wherein the splicing regulator comprises D4 and the linker comprises MC-β-glucuronide.

[1418] Item 887. The method of any one of Items 688 to 708, wherein the splicing regulator comprises D12:

[1419]

[1420] Item 888. The method of Item 887, wherein the splicing regulator comprises D12 and the linker comprises MC-Val-Cit-pABC.

[1421] Item 889. The method of Item 887, wherein the splicing regulator comprises D12 and the linker comprises MC-β-glucuronide.

[1422] Item 890. The method of any one of Items 688 to 708, wherein the splicing regulator comprises D15:

[1423]

[1424] Item 891. The method of Item 890, wherein the splicing regulator comprises D15 and the linker comprises MC-Val-Ala-pAB.

[1425] Item 892. The method of Item 719 or Item 720, wherein the pradienolide D or derivative comprises D4.

[1426] Item 893. The method of Item 719 or Item 720, wherein the pradienolide D or derivative comprises D12.

[1427] Item 894. The method of Item 727 or Item 728, wherein the aryl pramide diene lactone comprises D15.

[1428] Item 895. A neoantigen vaccine comprising at least one neoantigen peptide, wherein the at least one neoantigen peptide comprises a modified or novel neoantigen sequence induced by contacting neoplastic cells with an effective amount of a splicing regulator, an antibody-drug conjugate as described in any one of Items 776 to 868, or a composition as described in Item 869 or Item 870.

[1429] Item 896. A neoantigen vaccine comprising at least one neoantigen mRNA, wherein the at least one neoantigen mRNA encodes a modified or novel neoantigen sequence induced by contacting neoplastic cells with an effective amount of a splicing regulator, an antibody-drug conjugate as described in any one of Items 776 to 868, or a composition as described in Item 869 or Item 870.

[1430] Item 897. An antibody-drug conjugate having the structure

[1431]

[1432] wherein Ab is an antibody or antigen-binding fragment, and the antibody or antigen-binding fragment is covalently bound to the maleimide group of ADL1-D1 through the sulfur atom of the thiol group on the antibody or antigen-binding fragment.

[1433] Item 898. An antibody-drug conjugate having the structure

[1434]

[1435] wherein Ab is an antibody or antigen-binding fragment, the antibody or antigen-binding fragment is covalently bound to the maleimide group of ADL1-D4 through the sulfur atom of the thiol group on the antibody or antigen-binding fragment.

[1436] Item 899. An antibody-drug conjugate having the structure

[1437]

[1438] wherein Ab is an antibody or antigen-binding fragment, the antibody or antigen-binding fragment is covalently bound to the maleimide group of ADL1-D12 through the sulfur atom of the thiol group on the antibody or antigen-binding fragment.

[1439] Item 900. An antibody-drug conjugate having the structure

[1440]

[1441] wherein Ab is an antibody or antigen-binding fragment, and the antibody or antigen-binding fragment is covalently bound to the maleimide group of ADL5-D2 through the sulfur atom of the thiol group on the antibody or antigen-binding fragment.

[1442] Item 901. An antibody-drug conjugate having the structure

[1443]

[1444] wherein Ab is an antibody or antigen-binding fragment, and the antibody or antigen-binding fragment is covalently bound to the maleimide group of ADL5-D15 through the sulfur atom of the thiol group on the antibody or antigen-binding fragment.

[1445] Item 902. An antibody-drug conjugate having the structure

[1446]

[1447] wherein Ab is an antibody or antigen-binding fragment, and the antibody or antigen-binding fragment is covalently bound to the maleimide group of ADL13-D4 through the sulfur atom of the thiol group on the antibody or antigen-binding fragment.

[1448] Item 903. The antibody-drug conjugate of any one of Items 897 to 902, wherein the antibody or antigen-binding fragment targets cells expressing HER2.

[1449] Item 904. The antibody-drug conjugate of Item 903, wherein the antibody or antigen-binding fragment is an anti-HER2 antibody or antigen-binding fragment.

[1450] Item 905. An antibody-drug conjugate as described in Item 903 or Item 904, wherein the antibody or antigen-binding fragment comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) comprising 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) comprising the amino acid sequences of SEQ ID NO:4 (LCDR1), SEQ ID NO:5 (LCDR2) and SEQ ID NO:6 (LCDR3).

[1451] Item 906. An antibody-drug conjugate as described in any one of Items 903 to 905, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 19 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 20.

[1452] Item 907. An antibody-drug conjugate as described in any one of Items 903 to 906, wherein the antibody or antigen-binding fragment comprises a human IgG1 heavy chain constant region.

[1453] Item 908. The antibody-drug conjugate of any one of Items 903 to 907, wherein the antibody or antigen-binding fragment comprises a human Igκ light chain constant region. BRIEF DESCRIPTION OF THE DRAWINGS

[1454] Figure 1 Figure 2 shows the dose response of exemplary payload compounds in a competitive binding assay. Nuclear extracts from 293F cells overexpressing flag-tagged wild-type SF3B1 were immunoprecipitated with anti-SF3B1 antibody and scintillation proximity assay (SPA) bead mixture. Binding reactions contained the antibody-bead mixture and increasing concentrations of compound followed by 3 Competition with H-labeled pradienolide B (PB) probe. The y-axis represents the percent change in specific binding (% response) relative to the DMSO control (0%). Data are presented as mean ± standard deviation (SD).

[1455] Figure 2Figure 2 shows splicing modulation by exemplary payload compounds in an in vitro splicing assay. Nuclear extracts from HeLa S3 cells were incubated with Ad2.2 pre-mRNA and increasing concentrations of compound, followed by quantification of splicing modulation via RT-PCR. The Ad2.2 sequence is derived from an adenoviral Ad2 pre-mRNA substrate with modifications around the branch point sequence. The y-axis represents the percent change in splicing (% response) relative to the DMSO control (0%). Data are presented as mean ± SD.

[1456] Figure 3 The viability dose response of exemplary payload compounds is shown in HER2 amplified breast cancer cells (HCC1954). Cells were incubated with compounds for 144 hours (6 days) and The activity was measured in the reagent. Data are expressed as mean ± SD.

[1457] Figure 4 Results of a cell binding assay are shown. Binding of an exemplary HER2-ADC to JIMT1 cells was assessed by flow cytometry. Mean fluorescence intensity values ​​were measured to determine binding of the conjugate, followed by binding of a PE-labeled secondary antibody. Data are presented as mean ± SD.

[1458] Figure 5A Shown is the dose response of activity of an exemplary HER2-ADC in HER2-amplified breast cancer cells (HCC1954). Figure 5B Shown is the dose response of activity of an exemplary HER2-ADC in HER2-amplified gastric cancer cells (N87). Figure 5C Figure 2 shows the viability dose response of an exemplary HER2-ADC in HER2-amplified breast cancer cells (SKBR3). Cells were incubated with the conjugate for 144 hours (6 days) and The activity was measured in the reagent. Data are expressed as mean ± SD.

[1459] Figure 6 Figure 2 shows the dose response of the activity of an exemplary HER2-ADC in breast cancer cells (MCF7) that do not express HER2. Cells were incubated with the conjugate for 144 hours (6 days) and The activity was measured in the reagent. Data are expressed as mean ± SD.

[1460] Figure 7Shown are the results of an SLC25A19 splicing assay in HER2-amplified breast cancer cells (HCC1954). Cells were incubated with the conjugate for 24 hours, and splicing of the SLC25A19 transcript was measured in a real-time qPCR reaction using a specific Taqman primer-probe set. The y-axis represents the percent response (%) relative to the DMSO control (0%). Data are presented as mean ± SD.

[1461] Figure 8 Results of a bystander killing assay are shown. HER2-overexpressing H1568 cells (target positive) or luciferase-labeled H1568 cells (target negative) were treated with an exemplary HER2-ADC and plated alone or incubated together in co-culture for 144 hours (6 days). Reagent read plate. The y-axis represents the percentage (%) of response relative to the PBS control (100%). Data are expressed as mean ± SD.

[1462] Figure 9 Shown are tumor growth kinetics of CB17-SCID mice (6-10 animals / group) implanted with HCC1954 treated with a single intravenous dose of an exemplary HER2-ADC or a corresponding dose-matched payload. Tumor volume was measured twice weekly following treatment. Data are presented as mean ± standard error of the mean (SEM).

[1463] Figure 10 Figure 2 shows the activity dose response of an exemplary CD138-ADC in a multiple myeloma cell line expressing CD138. MOLP8 cells were incubated with the conjugate for 144 hours (6 days) and The activity was measured in the reagent. Data are expressed as mean ± SD.

[1464] Figure 11 Figure 5 shows the dose response of the activity of an exemplary EPH2A-ADC in a prostate cancer cell line expressing EPHA2. PC3 cells were incubated with the conjugate for 144 hours (6 days) and The activity was measured in the reagent. Data are expressed as mean ± SD.

[1465] Figure 12A and Figure 12B The results of an in vitro stability assay of an exemplary anti-HER2 ADC, AB185-ADL1-D1, are shown. The y-axis represents total antibody ( Figure 12A ) and the conjugated (intact) payload ( Figure 12B ); the x-axis represents time measured in hours at 37°C.

[1466] Figure 13Shown are plasma concentrations of an exemplary anti-HER2 ADC, AB185-ADL1-D1, following a single intravenous dose in CD17-SCID N87 tumor-bearing mice.

[1467] Figure 14 Schematic diagram showing exemplary RNA sequencing and protein ligandome experiments.

[1468] Figure 15 Schematic diagram showing an exemplary T-cell priming experiment.

[1469] Figure 16 Results of FACS analysis are shown. Monocytes were isolated from peripheral blood mononuclear cells (PBMC) and induced to differentiate into dendritic cells (DCs) by culturing in a cytokine cocktail. FACS was performed to verify the maturation of DCs from monocytes.

[1470] Figures 17A-17D Results of ELISpot assays are shown. Figure 17A An ELISpot plate is shown, indicating that neoantigen 1 triggers CD8+ T cell activation. Stimulation of CD8+ T cells was monitored by the secretion of IFNγ. Figure 17B Neoantigen 1 ELISpot plate ( Figure 17A ) Quantification of IFNγ spots (number of spots). Figure 17C An ELISpot plate is shown, indicating that neoantigen 3 triggers CD8+ T cell activation. Stimulation of CD8+ T cells was monitored by the secretion of IFNγ. Figure 17D Neoantigen 3 ELISpot plate ( Figure 17C Quantification of IFNγ spots in ).

[1471] Figure 18 A graph comparing the splicing potency (IC50 qPCR) and cellular potency (GI50 CTG) of an exemplary anti-HER2 ADC in HCC1954 breast cancer cells is shown. The values ​​shown are sized according to cell lethality and shaded according to the depth of the alternative splicing response.

[1472] Figure 19 A graph comparing the splicing potency (IC50 qPCR) and cellular potency (GI50 CTG) of an exemplary anti-HER2 ADC in N87 gastric cancer cells is shown. The values ​​shown are sized according to cell lethality and shaded according to the depth of the alternative splicing response.

[1473] Figure 20Figure 2 shows a graph comparing the potency and lethality of an exemplary anti-HER2 ADC (in HCC1954 breast cancer cells) with the stability and permeability of the corresponding payload. The values ​​shown are sized according to payload stability and shaded according to payload permeability.

[1474] Figure 21 Tumor growth kinetics of N87-implanted CB17-SCID mice (N=8 / group) treated intravenously with vehicle or 10 mg / kg trastuzumab, TDM1, or exemplary HER2-ADC Q7D for 2 cycles are shown. Data are presented as mean ± standard error of the mean (SEM) (mm 3 ).

[1475] Figure 22 Shown are changes in body weight of N87-implanted CB17-SCID mice (N=8 / group) treated intravenously with vehicle or 10 mg / kg trastuzumab, TDM1, or exemplary HER2-ADC Q7D for 2 cycles. Data are presented as mean ± standard error of the mean (SEM) (%).

[1476] Figure 23 Shown are tumor growth kinetics (left panel) and body weight changes (right panel) of N87-implanted CB17-SCID mice (N=8 / group) treated intravenously with vehicle or 10 mg / kg trastuzumab, TDM1, or exemplary HER2-ADC Q7D for 2 cycles. Data are expressed as mean ± SEM (tumor volume, mm 3 ) or mean ± SEM (body weight, %).

[1477] Figures 24A-24D Pharmacodynamic (PD) modulation of mRNA junctions in N87-implanted CB17-SCID mice treated intravenously for 2 cycles with vehicle or 10 mg / kg trastuzumab, TDM1, or the exemplary HER2-ADC Q7D is shown. RT-qPCR of FBXW5 (mature mRNA transcript) was monitored and shown in Figure 24A and Figure 24C RT-qPCR was used to monitor TAOK1 (new junction transcript) and is shown in Figure 24B and Figure 24D In 48 hours ( Figure 24A and Figure 24B ) or at a specified time ( Figure 24C and Figure 24D ) were collected (N=4 / group). Tumors were isolated for RNA extraction and RT-qPCR.

[1478] Figure 25 Schematic diagram showing an exemplary target indication analysis.

[1479] Figure 26 An exemplary bioconjugation scheme for preparing ADCs using splicing modulators is shown. DETAILED DESCRIPTION

[1480] The disclosed compositions and methods may be understood more readily by reference to the following detailed description taken in conjunction with the accompanying drawings, which form a part of this disclosure.

[1481] Throughout the disclosure, these descriptions refer to compositions and methods of using these compositions. When this disclosure describes or claims a feature or embodiment associated with a composition, such feature or embodiment also applies to the method of using the composition. Similarly, when this disclosure describes or claims a feature or embodiment associated with a method of using a composition, such feature or embodiment also applies to the composition.

[1482] When a range of values ​​is expressed, it includes embodiments using any specific value within the range. In addition, reference to a value stated in a range includes every value within the range. All ranges are inclusive of their endpoints and combinable. When a value is expressed as an approximation by using the antecedent "about," it will be understood that the specific value forms another embodiment. Unless the context clearly indicates otherwise, reference to a specific numerical value includes at least that specific value. Unless otherwise indicated in the specific context of its use, the use of "or" will mean "and / or." 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 will prevail.

[1483] It will be appreciated that certain features of the disclosed compositions and methods that are described herein for clarity in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, various features of the disclosed compositions and methods that are described for brevity in the context of a single embodiment may also be provided separately or in any subcombination.

[1484] definition

[1485] Throughout the specification and claims, various terms related to the description are used. Unless otherwise indicated, such terms shall have their ordinary meanings in the art. Other specifically defined terms should be interpreted in a manner consistent with the definitions provided herein.

[1486] As used herein, the singular forms "a," "an," and "the" include plural forms unless the context clearly dictates otherwise.

[1487] As will be apparent to the skilled artisan from the teachings contained herein, the terms "about" and "approximately" in the context of numerical values ​​and ranges refer to values ​​or ranges that are approximately or close to the stated value or range, such that the embodiment can be performed as intended, such as having a desired amount of nucleic acid or polypeptide in a reaction mixture. In some embodiments, about means ±10% of the numerical amount.

[1488] 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 modulators) linked to one or more antibodies or antigen-binding fragments and are defined by the following general formula: Ab-(LD) p (Formula I), wherein Ab=antibody or antigen-binding fragment, L=linker moiety, D=drug moiety (e.g., splicing regulator drug moiety), and p=number of drug moieties / antibody or antigen-binding fragment. ADCs comprising splicing regulator drug moieties may also be more specifically referred to herein as "antibodies loaded with splicing regulators" or "SMLAs." In ADCs comprising splicing regulator drug moieties, "p" refers to the number of splicing regulator compounds attached to the antibody or antigen-binding fragment. In some embodiments, the linker L may include a cleavable portion between the antibody or antigen-binding fragment and the therapeutic compound. In some embodiments, the linker L may include a cleavable portion that can be attached to one or both of the antibody or antigen-binding fragment and the therapeutic compound through one or more spacer units. In some embodiments, when a spacer unit connects a cleavable portion to a therapeutic compound, it is a self-ablating spacer unit. In other embodiments, the linker L does not include a cleavable portion and is a non-cleavable linker. In some embodiments, the linker L may include at least one spacer unit that can be directly attached to the antibody or antigen-binding fragment and the therapeutic compound. Exemplary cleavable and non-cleavable linkers are described and exemplified herein.

[1489] 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 thereof) through 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 heavy chain constant region (C H ). The light chain is composed of the light chain variable domain (V L ) and the light chain constant domain (C L) composition. For the purposes of this application, mature heavy and light chain variable domains each comprise three complementary determining regions (CDR1, CDR2, and CDR3) within four framework regions (FR1, FR2, FR3, and FR4) arranged from N-terminus to C-terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. An "antibody" can be naturally occurring or artificial, such as a monoclonal antibody produced by conventional hybridoma technology. 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. The antibody can be any of the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, or a subclass thereof (e.g., isotype IgG1, IgG2, IgG3, IgG4). The term further encompasses human antibodies, chimeric antibodies, humanized antibodies, and any modified immunoglobulin molecule that contains an antigen recognition site so long as it exhibits the desired biological activity (e.g., binding to target antigen, internalization in a cell expressing the target antigen).

[1490] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous antibody population, that is, except for the possible naturally occurring mutations that may exist in a small amount, the individual antibodies constituting the population are identical. Monoclonal antibodies are highly specific for a single antigenic epitope. In contrast, conventional (polyclonal) antibody preparations typically include multiple antibodies directed against (or specific for) different epitopes. The modifier "monoclonal" indicates the characteristics of an antibody obtained from a substantially homogeneous antibody population, and should not be construed as requiring antibody production by any ad hoc method. For example, the monoclonal antibody used according to the present disclosure can be obtained by the hybridoma method first described by Kohler et al. (1975) Nature [nature] 256:495, or can be obtained by recombinant DNA methods (see, for example, U.S. Patent number 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.

[1491] 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 one particular species or belonging to a particular antibody class or subclass, while the remainder of the chain or chains is identical or homologous to the corresponding sequence in an antibody derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they specifically bind to the target antigen and / or exhibit the desired biological activity.

[1492] As used herein, the term "human antibody" refers to an antibody produced by humans or an antibody having the amino acid sequence of an antibody produced by humans.

[1493] 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 the heavy and light chains correspond to those of an antibody derived from one species with the desired specificity, affinity, and activity, while the constant regions are homologous to antibodies derived from another species (e.g., humans) to minimize the immune response in the latter species.

[1494] As used herein, the term "humanized antibody" refers to an antibody form containing sequences from non-human (e.g., mouse) antibodies and human antibodies. Such antibodies are chimeric antibodies containing the minimum sequence derived from non-human immunoglobulin (NII). Typically, a humanized antibody will comprise substantially all of at least one and typically two variable domains, wherein all or substantially all of the hypervariable loops correspond to those of non-human immunoglobulin (NII), and all or substantially all of the framework (FR) regions are these regions of human immunoglobulin sequences. Humanized antibodies will optionally also comprise at least a portion of an immunoglobulin constant region (Fc) (typically a human immunoglobulin constant region). Humanized antibodies can be further modified by the replacement of residues in the Fv framework region and / or in the substituted non-human residues to improve and optimize antibody specificity, affinity, and / or activity.

[1495] 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, STEAP1). The antigen-binding fragment may also retain the ability to be internalized 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 a full-length antibody. Examples of binding fragments encompassed within the term "antigen-binding fragment" or "antigen-binding portion" of an antibody include (i) a Fab fragment, a V-binding ... L 、V H 、C L and C H1 (ii) a F(ab')2 fragment, a bivalent fragment consisting of two Fab fragments linked by a disulfide bond at the hinge region; (iii) a fragment consisting of V H and C H1 (iv) an Fd fragment consisting of a V domain of an antibodyL and V H (v) dAb fragments, which contain a single variable domain, such as V H domains (see, e.g., 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 and V of the Fv fragment L and V H are encoded by separate genes, but can be joined using recombinant methods with a synthetic linker that enables them to be made as a single protein chain, where V L With V H The regions are paired to form monovalent molecules (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 term "antigen-binding fragment" or "antigen-binding portion" of an antibody, and are known in the art as exemplary binding fragment types that can be internalized into cells when bound (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, scFv molecules can be incorporated into fusion proteins. Other forms of single-chain antibodies, such as diabodies, are also encompassed. Diabodies are bivalent bispecific antibodies in which V H and V L The domains 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 domains to pair with the complementary domains of another chain and create two antigen-binding sites (see, e.g., 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 skilled in the art, and these binding fragments are screened for utility (e.g., binding affinity, internalization) in the same manner as intact antibodies. Antigen-binding fragments can be prepared by cleavage of the intact protein, for example, by protease or chemical cleavage.

[1496] As used herein with respect to antibodies or antigen-binding fragments, "internalization" refers to that the antibody or antigen-binding fragment, when bound to a cell, is able to pass through the lipid bilayer membrane of the cell into an internal compartment (i.e., "internalization"), preferably into a degradation compartment in the cell. For example, an internalizing anti-HER2 antibody is an antibody that can enter a cell after being bound to HER2 on the cell membrane. In some embodiments, the antibody or antigen-binding fragment used in the ADC disclosed herein targets a cell surface antigen (e.g., HER2) and is an internalizing antibody or internalizing antigen-binding fragment (i.e., ADC is transferred across the cell membrane after antigen binding). In some embodiments, the internalizing antibody or antigen-binding fragment binds to a receptor on the cell surface. The internalizing antibody or internalizing antigen-binding fragment targeting a receptor on the cell membrane can induce receptor-mediated endocytosis. In some embodiments, the internalizing antibody or internalizing antigen-binding fragment enters the cell via receptor-mediated endocytosis.

[1497] As used herein with respect to an antibody or antigen-binding fragment, "non-internalizing" refers to an antibody or antigen-binding fragment that remains on the cell surface when bound to a cell. In some embodiments, the antibody or antigen-binding fragment used in the ADC disclosed herein targets a cell surface antigen and is a non-internalizing antibody or non-internalizing antigen-binding fragment (i.e., the ADC remains on the cell surface after antigen binding and does not transfer across the cell membrane). In some embodiments, the non-internalizing antibody or antigen-binding fragment binds to a non-internalizing recept...

Claims

1. An antibody-drug conjugate of formula (I), Ab-(L-D) p (I) in Ab is an antibody or antigen-binding fragment that targets neoplastic cells; D is D2; L is a linker that covalently links Ab to D; and p is an integer of 1-15.

2. The antibody-drug conjugate of claim 1, wherein the antibody or antigen-binding fragment targets cells expressing HER2.

3. The antibody-drug conjugate of claim 2, wherein the antibody or antigen-binding fragment is an anti-HER2 antibody or antigen-binding fragment.

4. The antibody-drug conjugate of claim 2 or claim 3, wherein the antibody or antigen-binding fragment comprises three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) comprising 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 complementary determining regions (LCDR1, LCDR2 and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2) and SEQ ID NO: 6 (LCDR3).

5. The antibody-drug conjugate of any one of claims 2 to 4, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 19 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

20.

6. The antibody-drug conjugate of any one of claims 2 to 5, wherein the antibody or antigen-binding fragment comprises a human IgG1 heavy chain constant region.

7. The antibody-drug conjugate of any one of claims 2 to 6, wherein the antibody or antigen-binding fragment comprises a human Ig kappa light chain constant region.

8. The antibody-drug conjugate of claim 1, wherein the antibody or antigen-binding fragment targets cells expressing CD138.

9. The antibody-drug conjugate of claim 8, wherein the antibody or antigen-binding fragment is an anti-CD138 antibody or antigen-binding fragment.

10. The antibody-drug conjugate of claim 8 or claim 9, wherein the antibody or antigen-binding fragment comprises three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) comprising the amino acid sequences of SEQ ID NO: 7 (HCDR1), SEQ ID NO: 8 (HCDR2) and SEQ ID NO: 9 (HCDR3); and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) comprising the amino acid sequences of SEQ ID NO: 10 (LCDR1), SEQ ID NO: 11 (LCDR2) and SEQ ID NO: 12 (LCDR3).

Images