Potent FGFR4-targeted antibody-drug conjugates and their use for treating cancers expressing FGFR4

Abstract

Highly potent antibody-drug conjugates (ADCs) targeting fibroblast growth factor receptor (FGFR4) are described. The ADCs contain an FGFR4-specific monoclonal antibody or antigen-binding fragment thereof conjugated to an anti-cancer drug, such as monomethyl auristatin E (MMAE) or exatecan. The ADCs exhibit selective cell killing for FGFR4-expressing cells in vitro, and significantly decrease tumor volume and increase survival in animal models of FGFR4-expressing tumors.

Description

[0001] 4239-111442-02POTENT FGFR4-TARGETED ANTIBODY-DRUG CONJUGATES AND THEIR USE FOR TREATING CANCERS EXPRESSING FGFR4 CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Application No.63 / 575,037, filed April 5, 2024, which is herein incorporated by reference in its entirety. FIELD This disclosure concerns fibroblast growth factor receptor 4 (FGFR4)-targeted antibody-drug conjugates (ADCs) that include an anti-FGFR4 monoclonal antibody or antigen-binding fragment thereof conjugated to either monomethyl auristatin E (MMAE) or exatecan. Use of the FGFR4- targeted ADCs to treat cancers that express FGFR4 is also described. INCORPORATION OF ELECTRONIC SEQUENCE LISTING The electronic sequence listing, submitted herewith as an XML file named 4239-111442- 02.xml (19,411 bytes), created on March 28, 2025, is herein incorporated by reference in its entirety. BACKGROUND Rhabdomyosarcoma (RMS) is the most common pediatric sarcoma, accounting for 3-4% of childhood and adolescent cancers (Shern, et al., J Clin Oncol 39:2859-2871, 2021). The current standard of care consists of surgery, chemotherapy, and radiation therapy, achieving a relapse-free survival rate of over 70% but with significant toxicity (Pacenta et al., J Clin Med 10:1416, 2021). However, the prognosis for patients with relapsed or metastatic disease remains poor, with survival rates of only 20 ~ 30% (Pacenta et al., J Clin Med 10:1416, 2021). Despite extensive clinical research, treatment strategies for RMS have remained largely unchanged over the past three decades (Lucas and Pappo, Cancer 125:3107-3110, 2019; Hawkins et al., J Clin Oncol 36:2770-2777, 2018). Therefore, there is an urgent need for novel therapies to improve outcomes for high-risk patients and reduce treatment-related toxicity. Fibroblast growth factor receptor 4 (FGFR4) has emerged as a promising immunotherapeutic target due to its high expression in RMS and minimal presence in normal tissues (Tian et al., Cell Rep Med 4:101212, 2023). In fusion-positive (FP) RMS, FGFR4 is a direct transcriptional target of the PAX3-FOXO1 fusion oncogene, leading to its elevated expression (Khan et al., Nat Med 7:673-679, 2001; Gryder et al., Cancer Discov 7:884-899, 2017). In fusion-negative (FN) RMS, FGFR4 is activated by mutations in approximately 10 -15% of cases (Shern, et al., J Clin Oncol 39:2859-2871, 2021; Shern et al., Cancer Discov 4:216-231, 2014; Brohl et al., Cell Rep 37:110047, 2021). These findings provided a rationale for the development of FGFR4-targeted therapeutics. A high-affinity FGFR4-specific monoclonal antibody (mAb) 3A11 was previously developed. When the 3A11 single-4239-111442-02chain variable fragment (scFv) was incorporated into a chimeric antigen receptor (CAR) format, FGFR4-targeted CAR T cells exhibited potent anti-RMS activity (Tian et al., Cell Rep Med 4:101212, 2023). Furthermore, a Phase I dose-escalation clinical trial using FGFR4-targeted CAR T cells to treat patients with recurrent or refractory RMS is planned at NCI (NCT06865664). In addition to RMS, other malignancies that also have high FGFR4 expression include pediatric cancers such as hepatoblastoma, yolk sac tumors, and desmoplastic small round cell tumors, as well as adult cancers like hepatocellular carcinoma (HCC), cholangiocarcinoma (CHOL), adrenocortical carcinoma (ACC), and certain breast cancer subtypes (Tian et al., Cell Rep Med 4:101212, 2023). Antibody-drug conjugates (ADCs) represent a promising alternative immune therapy, leveraging the specificity of monoclonal antibodies to deliver potent cytotoxic agents directly to tumor cells (Thomas et al., Lancet Oncol 17:e254-e262, 2016). ADCs have demonstrated successes in both hematologic and solid malignancies, now with 14 of them approved by the FDA in US (Fu et al., Signal Transduct Target Ther 7:93, 2022). Compared to CAR T-cell therapy, ADCs offer advantages such as immediate availability, broader patient applicability, fewer immune-related side effects, simpler manufacturing, and the ability to give multiple doses (Tacchetti et al., Expert Rev Anticancer Ther 24:379-395, 2024). SUMMARY Highly potent antibody-drug conjugates (ADCs) targeting FGFR4 are described. The ADCs contain the FGFR4-specific monoclonal antibody 3A11 or a chimeric or humanized version thereof, or an antigen-binding fragment thereof. The disclosed ADCs exhibit selective cell killing for FGFR4- expressing cells in vitro. The ADCs also significantly decrease tumor volume and increase survival in animal models of FGFR4-expressing tumors. Provided herein are ADCs that include a monoclonal antibody or antigen-binding fragment thereof that specifically binds FGFR4, and a drug conjugated to the antibody or antigen-binding fragment. The monoclonal antibody or antigen-binding fragment includes a variable heavy (VH) domain and a variable light (VL) domain, wherein the VH domain includes the heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 sequences of the VH domain of antibody 3A11 (SEQ ID NO: 1) or a humanized 3A11 (SEQ ID NO: 11) and the VL domain includes the light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3 sequences of the VL domain of antibody 3A11 (SEQ ID NO: 2). In some aspects, the drug includes monomethyl auristatin E (MMAE). In other aspects, the drug includes exatecan or an exatecan derivative. In some aspects, the ADCs further include a linker connecting the antibody or antigen- binding fragment to the drug. In some examples, the linker includes valine-citruline-p- aminocarbamate (VC-PABC). In other examples, the linker includes mpGlyAsnAsn, mpGlyAsnAsnGly, mpGlyAsnAsn(beta-Ala), or mpGlyAsnAsn(gamma-aminobutyric acid (GABA). In some aspects, the monoclonal antibody or antigen-binding fragment further includes at least one4239-111442-02constant region, such as at least one human constant region. In some examples, the antibody includes human IgG1 heavy chain and / or light chain constant regions. Also provided herein are compositions that include a FGFR4-targeted ADC and a pharmaceutically acceptable carrier. Further provided are methods of treating a FGFR4-expressing cancer in a subject, and methods of inhibiting tumor growth or metastasis of a FGFR4-expressing cancer in a subject. In some aspects, the methods include administering to the subject a therapeutically effective amount of an ADC or composition disclosed herein. The foregoing and other features of this disclosure will become more apparent from the following detailed description of several aspects which proceeds with reference to the accompanying figures. BRIEF DESCRIPTION OF THE DRAWINGS FIGS.1A-1B: Characterization of 3A11-mcValCit-PABC-MMAE by high performance liquid chromatography-mass spectrometry (HPLC-MS) (FIG.1A) and size exclusion chromatography (SEC) (FIG.1B). FIGS.2A-2B: Characterization of anti-HEL-mcValCit-PABC-MMAE by HPLC-MS (FIG. 2A) and SEC (FIG.2B). FIGS.3A-3C: Characterization of 3A11-mpGlyAsnAsn(beta-Ala)-Exatecan by HPLC-MS (FIG.3A), SEC (FIG.3B), and hydrophobic interaction chromatography (HIC) (FIG.3C). FIGS.4A-4C: Characterization of anti-HE-mpGlyAsnAsn(beta-Ala)-Exatecan by HPLC-MS (FIG.4A), SEC (FIG.4B), and HIC (FIG.4C). FIG.5: FGFR4 surface expression by various cell lines. Expression levels of FGFR4 on RMS cell lines (RMS559, RD, RH30, JR, SCMC and RH4), FGFR4-knockout cell lines (RH30- FGFR4KO and RH4-FGFR4KO), a breast cancer cell line (MDA-MB-453), a liver cancer cell line (Huh7), and fibroblast 7250 cells was measured by flow cytometry (left). Surface FGFR4 molecule numbers per cell for the indicated cell lines was determined by phycoerythrin (PE) quantitation beads (right). FIGS.6A-6C: Internalization of 3A11 mAb is significantly correlated with the FGFR4 expression level on RMS cell surface. (FIG.6A) Internalized 3A11 mAb is trafficked into endolysosomes in FGFR4-expressing RMS cells. Representative images of FGFR4-expressing and FGFR4 KO RMS cells treated with 2.93 nM (0.44 µg / mL) INCUCYTE FabFluor-α-FGFR4 (3A11, top two rows) or FabFluor-IgG1 control (bottom two rows) antibodies after 24 hours incubation. High-definition phase-contrast and red fluorescence images were acquired every 30 minutes over 24 hours using a 10× objective. (FIG.6B) Time-course analysis of FabFluor-α-FGFR4 antibody internalization in RMS cell lines with varying FGFR4 expression levels was quantified as a ratio of4239-111442-02areas between the red fluorescent and phase contrast objects at each time point. Data points on the normalized fluorescence area curve represent the mean ± SD of three replicates. (FIG.6C) Correlation between FGFR4 expression levels and α-FGFR4 antibody internalization in a fibroblast (7250) and RMS cell lines. Simple linear regression analysis was used to determine the R² and p-value. Dots represent cell lines. Solid line is the regression fitting curve. Dotted lines represent 95% confidence intervals. NNβA-exatecan FIGS.7A-7D: FGFR4-targeted antibody-drug conjugates (ADCs) exhibit specific but distinct killing activities in RMS cells. (FIG.7A) Chemical structures of the linkers and payloads used in the two FGFR4-targeted ADCs: α-FGFR4-vc-MMAE (top) and α-FGFR4-NNβA-exatecan (bottom). (FIG.7B) Dose-response cell viability curves of RMS cell lines with varying FGFR4 expression levels following 120 hours of treatment with α-FGFR4-vc-MMAE and α-FGFR4-NNβA-exatecan, or their controls, α-HEL-vc-MMAE and α-HEL-NNβA-exatecan. X-axis, concentrations of ADC. The numbers of FGFR4 surface molecules per cell are below each cell line name. The panel is arranged according to FGFR4 expression levels across cell lines. Cell viability was assessed using a CellTiter- Glo assay. Results are presented as mean ± SEM (n = 3). (FIGS.7C and 7D) Correlation analysis of MMAE-based ADC potency (FIG.7C) or Exatecan-based ADC potency (FIG.7D) with FGFR4 expression levels, α-FGFR4 antibody internalization efficiency, and drug sensitivity in RMS cell lines. Simple linear regression was performed to assess these relationships, highlighting significant dependence of ADC efficacy on FGFR4 expression and internalization rather than intrinsic drug sensitivity. Dots represents cell lines. Solid line is regression fitting curve. Dotted lines represent 95% confidence intervals. FIGS.8A-8F: α-FGFR4-vc-MMAE induces apoptosis via PARP cleavage and bystander killing, and α-FGFR4-NNβA-exatecan induces apoptosis through DNA damage in FGFR4-expressing cells. (FIG.8A) PARP cleavage was induced in RMS559 and RH4 cells after 24-hour treatment with 6.67 nM (1 µg / mL) α-FGFR4-vc-MMAE, but not in RH4 FGFR4-knockout (KO) cells. PARP cleavage was not observed in untreated cells or control treatments with 3A11 naked antibody or α- HEL-vc-MMAE. Positive controls are cells treated with MMAE alone, demonstrating PARP cleavage. (FIG.8B) Relative caspase-3 / 7 activity in RMS559, RH4, and RH4 FGFR4 KO cells treated with 6.67 nM (1 µg / mL) α-FGFR4-vc-MMAE or controls for 24 hours. Results are presented as the mean ± SD of three independent experiments. Unpaired t-tests were performed to calculate the p-value. *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.001; ****p ≤ 0.0001; ns: no significant difference. (FIGS. 8C and 8D) α-FGFR4-NNβA-exatecan induces DNA damage and apoptosis in FGFR4-expressing cells. RMS559, RH4, and RH4 FGFR4 KO cells were treated with 6.67 nM (1 µg / mL) α-FGFR4- NNβA-exatecan or controls for 24, 48, or 72 hours. DNA damage markers (phosphorylated Chk1 and γH2A.X) and apoptosis markers (cleaved PARP and active caspase-3) were detected by Western blotting (FIG.8C) and flow cytometry (FIG.8D) at time points as shown. Percentages of γH2A.X+ and active caspase-3+ cells were quantified from the singlets’ histogram gating in panel FIG.8D.4239-111442-02(FIG.8E) Representative flow cytometry data showing the ratio of FGFR4-positive RH4 cells to FGFR4-negative RH4-FGFR4 KO cells after 5 days of coculture and treatment with 11 nM α-FGFR4- vc-MMAE, 22 nM α-FGFR4-Exatecan ADCs, or matched isotype control ADCs. (FIG.8F) Quantification of cell numbers determined by flow cytometry using counting beads. Each bar represents the mean ± SD (n = 3). FIGS.9A-9D: (FIG.9A) Serum concentration-time profile of free MMAE (exatecan not detected), quantified by LC-MS / MS following a single intravenous dose of ADC (3 mg / kg for MMAE-based, 10 mg / kg for exatecan-based; n = 3). (FIGS.9B-9C) Pharmacokinetic (PK) profiles of conjugated drug (FIG.9B) levels, and total IgG (FIG.9C) measured via Meso Scale Discovery (MSD) assay, after administration of ADC. Data represent mean ± SEM. (FIG.9D) Summary of pharmacokinetic parameters for MMAE- and exatecan-based ADCs, analyzed via non-compartmental pharmacokinetic modeling using Phoenix WinNonlin Version 8.4. Parameters include half-life (T1 / 2), area under the curve (AUC), clearance (CL), volume of distribution (Vd), and steady-state volume of distribution (Vss). FIGS.10A-10I: α-FGFR4-NNβA-exatecan demonstrates a superior potency compared to α- FGFR4-vc-MMAE in the aggressive RMS559 subcutaneous xenograft model. (FIG.10A) Designs to test the efficacy of α-FGFR4-vc-MMAE (top) and α-FGFR4-NNβA-exatecan (bottom) in a RMS559 subcutaneous xenograft model. Treatments were initiated (arrows) when tumors reached an average volume of ~100 mm³. (FIGS.10B and 10C) Tumor growth curves for RMS559 xenografts after treatment with a single cycle of 3 mg / kg α-FGFR4-vc-MMAE (FIG.10B, n = 10 per group) or two doses of 10 mg / kg α-FGFR4-NNβA-exatecan (FIG.10C, n = 8 per group). Statistical analysis using mixed-effects models determined significant differences between treatment and control groups. ****p ≤ 0.0001. (FIGS.10D and 10E) Kaplan-Meier survival curves for mice treated with α-FGFR4-vc- MMAE (FIG.10D, n = 10 per group) or α-FGFR4-NNβA-exatecan (FIG.10E, n = 8 per group). Statistical significance: **p = 0.0092, ****p ≤ 0.0001 in D; *p = 0.0195, ****p ≤ 0.0001 in FIG. 10E. (FIGS.10F and 10G) Immunohistochemistry (IHC) staining for FGFR4, proliferation marker Ki-67, and apoptosis marker cleaved caspase-3 in RMS559 tumors. Tumors were harvested 24 hours after a single dose of 3 mg / kg α-FGFR4-vc-MMAE (FIG.10F) or 72 hours after 10 mg / kg α-FGFR4- NNβA-exatecan (FIG.10G). Representative images for each treatment are shown. Scale bar: 100 μm. (FIGS.10H and 10I) Quantification signals of the IHC results, including FGFR4 membrane H-scores (left panels), Ki-67-positive cell percentages (middle panels), and cleaved caspase-3-positive pixel percentages (right panels) in RMS559 tumors treated with α-FGFR4-vc-MMAE (FIG.10H) or α- FGFR4-NNβA-exatecan (FIG.10I). Data are presented as means ± SD. Statistical significance was determined using one-way ANOVA. *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.001; ****p ≤ 0.0001; ns: not significant. FIGS.11A-11J: α-FGFR4-NNβA-exatecan exhibits greater potency than α-FGFR4-vc- MMAE in FP-RMS CDX and PDX models. (FIG.11A) Experimental design to evaluate the efficacy4239-111442-02of α-FGFR4-vc-MMAE (top) and α-FGFR4-NNβA-exatecan (bottom) in a RH4 subcutaneous xenograft model. Treatments were initiated (arrows) when tumors reached an average size of ~100 mm³. (FIGS.11B and 11C) Tumor growth curves for RH4 xenografts treated with a single cycle of 3 mg / kg α-FGFR4-vc-MMAE (FIG.11B, n = 10 per group) or 10 mg / kg α-FGFR4-NNβA-exatecan (FIG.11C, n = 5 per group) over time. Statistical test between groups uses mixed-effects models. ****p ≤ 0.0001. (FIGS.11D and 11E) Kaplan-Meier survival analysis of mice treated with α- FGFR4-vc-MMAE (FIG.11D, n = 10 per group) and α-FGFR4-NNβA-exatecan (FIG.11E, n = 5 per group). **p = 0.0038, ***p = 0.0006 in FIG.11D; **p = 0.0035 for Vehicle versus α-FGFR4-NNβA- exatecan or Vehicle versus α-HEL-NNβA-exatecan; **p = 0.0019 for α-FGFR4-NNβA-exatecan versus α-HEL-NNβA-exatecan in FIG.11E. (FIG.11F) Experimental design to evaluate the efficacy of α-FGFR4-vc-MMAE (top) and α-FGFR4-NNβA-exatecan (bottom) in a subcutaneous FP-RMS patient-derived xenograft (PDX) model. Treatments were initiated (arrows) when tumors reached an average size of ~100 mm³. (FIGS.11G and 11H) Tumor growth curves for FP-RMS PDX treated with a single cycle of 3 mg / kg α-FGFR4-vc-MMAE (FIG.11G, n = 5 per group) or 3 mg / kg α-FGFR4- NNβA-exatecan (FIG.11H, n = 8). Mixed-effects models were used for statistical analysis. ****p ≤ 0.0001. (FIGS.11I and 11J) Kaplan-Meier survival analysis of mice treated with α-FGFR4-vc- MMAE (I, n = 5) or α-FGFR4-NNβA-exatecan (J, n = 8). *p = 0.0481 for Vehicle versus α-HEL-vc- MMAE, **p = 0.0020 for Vehicle versus α-FGFR4-vc-MMAE, **p = 0.0018 for α-FGFR4-vc- MMAE versus α-HEL-vc-MMAE in FIG.11I; **p = 0.0017 for Vehicle versus α-HEL-NNβA- exatecan, ****p ≤ 0.0001in FIG.11J. FIGS.12A-12G: FGFR4-targeted ADCs exhibit efficacy in FGFR4-expressing breast and liver cancers. (FIG.12A) FGFR4 mRNA expression across pediatric and adult solid tumors from TCGA datasets, highlighting high expression in liver hepatocellular carcinoma (LIHC) and a subset of breast cancer (BRCA). Tumor type abbreviations follow TCGA nomenclature (gdc.cancer.gov / resources-tcga-users / tcga-code-tables / tcga-study-abbreviations). Expression levels are represented as log₂(TPM+1) (TPM: Transcripts Per Million) for FGFR4. The number and percentage of samples with high FGFR4 expression are indicated above the dashed line (cutoff = 6.5). (FIG.12B) Representative immunohistochemistry (IHC) images showing moderate, mild, and negative FGFR4 staining in breast (top row) and liver (bottom row) cancers. Scale bar: 50 μm. A table summarizes FGFR4 positivity in breast and liver cancer tissue microarrays (TMAs). (FIG.12C) Flow cytometry analysis of FGFR4 expression in breast cancer cell lines (MDA-MB-453, CAMA-1, BT- 474, SKBR3, and MDA-MB-134 IV) and liver cancer cell lines (Huh7, Hep3B, and HepG2). Surface FGFR4 molecule numbers per cell are quantified using PE calibration beads (table). (FIG.12D) Evaluation of the cytotoxic activity of α-FGFR4-vc-MMAE and α-FGFR4-NNβA-exatecan against breast and liver cancer cell lines using cell viability assays. Results are presented as means ± SEM. (FIG.12E) Experimental design to test the efficacy for two ADCs in a subcutaneous breast cancer CDX model using MDA-MB-453 cells. Treatments were initiated (downward arrows for α-FGFR4-4239-111442-02vc-MMAE, upward arrows for α-FGFR4-NNβA-exatecan) when tumors reached an average size of ~100 mm³. (FIG.12F) CDX tumor growth curves. Treatments (downward arrows for α-FGFR4-vc- MMAE, upward arrows for α-FGFR4-NNβA-exatecan) started when tumor size reached ~100 mm³ (n = 5 per group). **p ≤ 0.0001. (FIG.12G) Kaplan-Meier survival analysis of the MDA-MB-453 xenograft study in (FIG.12F). Log-rank test was performed for p-values. **p = 0.0034 for Vehicle versus α-FGFR4-vc-MMAE, **p = 0.0021 for α-FGFR4-vc-MMAE versus α-HEL-vc-MMAE, ns: no significant difference; *p = 0.0412 for vehicle versus α-HEL-NNβA-exatecan; **p = 0.0018 for α- FGFR4-vc-Exatecan versus α-HEL-NNβA-exatecan, **p = 0.0034 for vehicle versus α-FGFR4-vc- Exatecan, α-FGFR4-vc-Exatecan versus α-HEL-NNβA-exatecan. FIGS.13A-13C: Sensitivity of RMS cell lines to MMAE or Exatecan. (FIGS.13A-13B) Cell viability assays assessing the cytotoxic effects of free MMAE (FIG.13A) and free Exatecan (FIG.13B) on RMS cell lines following 120 hours of treatment. Data are presented as mean ± SEM (n = 3). (FIG.13C) IC₅₀ values of MMAE and Exatecan for each RMS cell line are summarized in the table. FIGS.14A-14H: Dose-finding study identifies 3 mg / kg α-FGFR4-vc-MMAE as a potent and tolerable dose in the RMS559 subcutaneous model. (FIG.14A) Schematic of the dose-finding study for α-FGFR4-vc-MMAE in the RMS559 model. Treatments (arrows) were initiated when tumors reached an average size of ~100 mm³. (FIG.14B) Kaplan-Meier survival analysis of mice treated with α-FGFR4-vc-MMAE at different doses (n = 5 per group). Log-rank test p-values: *p = 0.0128 for 1 mg / kg versus 3 mg / kg α-FGFR4-vc-MMAE, **p = 0.0035 for 0.3 mg / kg versus 1 mg / kg α-FGFR4- vc-MMAE or 0.3mg / kg versus 3 mg / kg α-FGFR4-vc-MMAE, **p = 0.0077 for 1 mg / kg α-FGFR4- vc-MMAE versus 1mg / kg α-HEL-vc-MMAE. (FIGS.14C-14E) Tumor growth curves for RMS559 xenografts treated with a single cycle of 0.3 mg / kg (FIG.14C), 1 mg / kg (FIG.14D), or 3 mg / kg α- FGFR4-vc-MMAE (FIG.14E). Statistical analysis was performed using mixed-effects models. ****p ≤ 0.0001; ns: not significant. (FIG.14F-14H) Body weight changes in mice following the indicated doses of α-FGFR4-vc-MMAE in the RMS559 model. FIGS.15A-15D: Dose-finding study identifies 10 mg / kg α-FGFR4-NNβA-exatecan as an effective and tolerable dose in the RMS559 subcutaneous model. (FIG.15A) Schematic of the dose- finding study for α-FGFR4-NNβA-exatecan in the RMS559 model. Treatments (arrow) was initiated when tumors reached an average size of ~100 mm³. (FIG.15B) Tumor growth curves for RMS559 xenografts treated with a single dose of 3 mg / kg or 10 mg / kg α-FGFR4-NNβA-exatecan. Statistical analysis was performed using mixed-effects models. ****p ≤ 0.0001. (FIG.15C) Kaplan-Meier survival analysis of mice treated with α-FGFR4-NNβA-exatecan at different doses (n = 5 per group). Log-rank test p-values: **p = 0.0027, ***p = 0.0009. (FIG.15D) Body weight changes in mice treated with the indicated doses of α-FGFR4-NNβA-exatecan in the RMS559 model. FIGS.16A-16D: FP-RMS PDX is very sensitive to a single 10 mg / kg dose of α-FGFR4- NNβA-exatecan. (FIG.16A) Schematic of testing the efficacy of 10 mg / kg α-FGFR4-NNβA-4239-111442-02exatecan in FP-RMS PDX model. Treatment (arrow) was initiated when tumors reached an average size of ~100 mm³. (FIG.16B) Tumor growth curves of FP-RMS PDX xenografts treated with α- FGFR4-NNβA-exatecan (10 mg / kg, single dose). Statistical analysis was performed using mixed- effects models (****p ≤ 0.0001). (FIG.16C) Kaplan-Meier survival analysis of mice treated with α- FGFR4-NNβA-exatecan or controls (n = 5 per group). Log-rank test p-values: *p = 0.0494 for α- FGFR4-NNβA-exatecan versus α-HEL-NNβA-exatecan, *p = 0.0310 for vehicle versus α-HEL- NNβA-exatecan; **p = 0.0020. (FIG.16D) Body weight changes in mice treated with α-FGFR4- NNβA-exatecan or controls in the FP-RMS PDX model. FIGS.17A-17C: Limited efficacy of FGFR4-targeted ADCs and free payloads in liver cancer cell lines (Hep3B and HepG2). (FIG.17A) Cell viability assays assessing the cytotoxic effects of α- FGFR4-vc-MMAE and α-FGFR4-NNβA-exatecan on Hep3B and HepG2 liver cancer cell lines. Data are presented as mean ± SEM. (FIG.17B) Cytotoxicity assays evaluating the effects of free MMAE (left) and Exatecan (right) on breast and liver cancer cell lines following 120-hour treatment. Data are shown as mean ± SEM (n = 3). (FIG.17C) IC₅₀ values of free MMAE and Exatecan in each breast and liver cancer cell line, summarized in the table. FIG.18: ELISA analysis of chimeric 3A11 (c3A11) and humanized 3A11 (h3A11) antibody binding to FGFR4 proteins from different species. The chimeric and humanized 3A11 antibodies were tested for binding to human FGFR4 (hFGFR4), rhesus FGFR4 (rheFGFR4), mouse FGFR4 (mFGFR4) and rat FGFR4 (rFGFR4). h3A11 and c3A11 had similar binding affinity for hFGFR4 and rheFGFR4, but did not bind mFGFR4 or rFGFR4. FIGS.19A-19D: Biolayer interferometry (BLI) analysis of c3A11 and h3A11 binding to human and rhesus FGFR4 proteins. Binding avidity was evaluated using a 1:2 binding model and global fitting analysis. The y-axis is the signal for association for 600 seconds and then dissociation for 600 seconds. (FIG.19A) Binding avidity of c3A11 to human FGFR4. The dissociation constant (KD) was calculated to be 67.18 pM. (FIG.19B) Binding avidity of h3A11 to human FGFR4 (KD of <1 pM). (FIG.19C) Binding avidity of c3A11 to rhesus FGFR (KD of <1 pM). (FIG.19D) Binding avidity of h3A11 to rhesus FGFR4 (KD of 28.01 pM). SEQUENCES The nucleic acid and amino acid sequences listed in the accompanying sequence listing are shown using standard letter abbreviations for nucleotide bases, and single letter code for amino acids, as defined in 37 C.F.R.1.822. Only one strand of each nucleic acid sequence is shown, but the complementary strand is understood as included by any reference to the displayed strand. In the accompanying sequence listing: SEQ ID NO: 1 is the amino acid sequence of the 3A11 variable heavy (VH) domain. SEQ ID NO: 2 is the amino acid sequence of the 3A11 variable light (VL) domain. SEQ ID NOs: 3-8 are amino acid sequences of the CDRs of antibody 3A11.4239-111442-02SEQ ID NO: 9 is the amino acid sequence of a humanized 3A11 (h3A11-1) VH domain. SEQ ID NO: 10 is the amino acid sequence of a humanized 3A11 (h3A11-1) VL domain. SEQ ID NO: 11 is the amino acid sequence of a humanized 3A11 (h3A11-2) VH domain. SEQ ID NO: 12 is the amino acid sequence of a humanized 3A11 (h3A11-2) VL domain. SEQ ID NO: 13 is the amino acid sequence of a humanized 3A11 (h3A11-3) VH domain. SEQ ID NO: 14 is the amino acid sequence of a humanized 3A11 (h3A11-3) VL domain. SEQ ID NO: 15 is the amino acid sequence of 3A11 in scFv format. SEQ ID NO: 16 is the amino acid sequence of h3A11-1 in scFv format. SEQ ID NO: 17 is the amino acid sequence of a human IgG1 heavy chain constant region. SEQ ID NO: 18 is the amino acid sequence of a human IgG1 light chain constant region. SEQ ID NO: 19 is the amino acid sequence of a HCDR3 from a humanized version of 3A11. SEQ ID NO: 20 is the nucleic acid sequence of a FGFR4-guide sequence. DETAILED DESCRIPTION I. Introduction Antibody-drug conjugates (ADCs) combine the specificity of monoclonal antibodies with the cytotoxic potency of chemotherapy drugs, resulting in a targeted therapy that can selectively deliver potent anticancer agents to tumor cells while sparing healthy tissues. FGFR4 is a cell-surface receptor tyrosine kinase that is highly expressed in, for example, rhabdomyosarcoma (RMS), hepatocellular carcinoma (HCC), hepatoblastoma (HBL), desmoplastic small round cell tumors (DSRCT), adrenocortical carcinoma (ACC), gastric adenocarcinoma, and some breast cancers. For ADC payload selection, RMSs are often sensitive to both microtubule and topoisomerase I (Topo I) inhibitors, which are used as frontline and relapse therapies (Pacenta et al., J Clin Med 10:1416, 2021). Microtubule inhibitors disrupt mitotic spindle formation by binding to tubulin and preventing polymerization (Perez, Mol Cancer Ther 8:2086-2095, 2009), while Topo I inhibitors induce cell apoptosis by stabilizing Topo I-DNA complexes, leading to DNA replication stress and cell-cycle arrest (Pommier, Nat Rev Cancer 6:789-802, 2006). In addition, ADCs utilizing microtubule inhibitors exert strong bystander effects (Khera et al., Mol Cancer Ther 21:310-321, 2022), making them particularly effective in antigen-heterogeneous tumors. However, systemic toxicities can limit their therapeutic window (Wolska-Washer and Robak, Drug Saf 42:295-314, 2019; Coats et al., Clin Cancer Res 25:5441-5448, 2019; Donaghy, MAbs 8:659-671, 2016). Conversely, Topo I inhibitor-based ADCs with enhanced linker stability offer improved efficacy and therapeutic windows in solid tumors (Bardia et al., N Engl J Med 384:1529-1541, 2021; Modi et al., J Clin Oncol 38:1887-1896, 2020). Among FDA-approved ADCs, the most common platform (5 of 14) utilizes a valine- citrulline-p-aminocarbamate (VC-PABC) linker to conjugate with monomethyl auristatin E (MMAE) (Fu et al., Signal Transduct Target Ther 7:93, 2022). Exatecan, a potent Topo I inhibitor, is used in an4239-111442-02FDA-approved HER2-targeting ADC trastuzumab deruxtecan (Enhertu) (Harbeck et al., Nat Med 30:3717-3727, 2024). In the present disclosure, two 3A11 ADCs were developed using two different linkers and payloads, one with a protease-cleavable valine-citrulline-p-aminobenzyl carbamate (VC- PABC) linker conjugated with MMAE (α-FGFR4-vc-MMAE); the other with a legumain-cleavable mpGlyAsnAsn(βAla) linker targeted by lysosomal asparaginyl endopeptidase (Miller et al., Bioconjug Chem 32:842-858, 2021) conjugated with Exatecan (α-FGFR4-NNβA-exatecan). Their efficacy was evaluated in several RMS models in vitro and in vivo and it was found that the potency of these FGFR4 ADCs correlated with FGFR4 expression and 3A11-mediated internalization. While both ADCs exhibited comparable in vitro efficacy, the Exatecan-based ADC demonstrated superior anti- tumor activity in multiple aggressive FN-RMS mouse models including RMS559 cell line-derived xenograft (CDX), FP-RMS RH4 CDX, and an FP-RMS patient-derived-xenograft (PDX) model. Furthermore, the efficacy of these FGFR4-targeted ADCs was also evaluated in breast and liver cancer models. Notably, both ADCs exhibited effective tumor control. Exatecan-based FGFR4 ADC provided additional prolonged tumor suppression in breast cancer models expressing high FGFR4, supporting its clinical utility in other malignancies with high FGFR4 expression. II. Abbreviations ACC adrenocortical carcinoma ADC antibody-drug conjugate ARMS alveolar rhabdomyosarcoma CDR complementarity determining region DSRCT desmoplastic small round cell tumor ERMS embryonal rhabdomyosarcoma FACS fluorescence activated cell sorting FGFR4 fibroblast growth factor receptor 4 HBL hepatoblastoma HCC hepatocellular carcinoma HEL hen egg lysozyme HIC hydrophobic interaction chromatography HPLC high performance liquid chromatography KO knockout LC-MS liquid chromatography-mass spectrometry MFI mean fluorescence intensity MS mass spectrometry MMAE monomethyl auristatin E PARP poly(ADP-ribose) polymerase PE phycoerythrin4239-111442-02RMS rhabdomyosarcoma VC-PABC valine-citruline-p-aminocarbamate VH variable heavy VL variable light III. Summary of Terms Unless otherwise noted, technical terms are used according to conventional usage. Definitions of many common terms in molecular biology may be found in Krebs et al. (eds.), Lewin’s genes XII, published by Jones & Bartlett Learning, 2017. As used herein, the singular forms “a,” “an,” and “the,” refer to both the singular as well as plural, unless the context clearly indicates otherwise. For example, the term “an antigen” includes singular or plural antigens and can be considered equivalent to the phrase “at least one antigen.” As used herein, the term “comprises” means “includes.” It is further to be understood that any and all base sizes or amino acid sizes, and all molecular weight or molecular mass values, given for nucleic acids or polypeptides are approximate, and are provided for descriptive purposes, unless otherwise indicated. Although many methods and materials similar or equivalent to those described herein can be used, particular suitable methods and materials are described herein. In case of conflict, the present specification, including explanations of terms, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. To facilitate review of the various aspects, the following explanations of terms are provided: Administration: To provide or give a subject an agent, such as a monoclonal antibody or ADC provided herein, by any effective route. Exemplary routes of administration include, but are not limited to, oral, injection (such as subcutaneous, intramuscular, intradermal, intraperitoneal, intravenous, intraprostatic, and intratumoral), sublingual, rectal, transdermal, intranasal, vaginal, and inhalation routes. Adrenocortical carcinoma (ACC): A type of cancer in which malignant cells form in the outer layer of the adrenal gland. ACC is also referred to as cancer of the adrenal cortex. Antibody: A polypeptide ligand comprising at least one variable region that recognizes and binds (such as specifically recognizes and specifically binds) an epitope of an antigen (such as FGFR4). Mammalian immunoglobulin molecules are composed of a heavy (H) chain and a light (L) chain, each of which has a variable region, termed the variable heavy (VH) domain and the variable light (VL) domain, respectively. Together, the VH domain and the VL domain are responsible for binding the antigen recognized by the antibody. There are five main heavy chain classes (or isotypes) of mammalian immunoglobulin, which determine the functional activity of an antibody molecule: IgM, IgD, IgG, IgA and IgE. Antibody isotypes not found in mammals include IgX, IgY, IgW and IgNAR. IgY is the primary antibody produced by birds and reptiles and is functionally similar to4239-111442-02mammalian IgG and IgE. IgW and IgNAR antibodies are produced by cartilaginous fish, while IgX antibodies are found in amphibians. Antibody variable regions contain "framework" regions and hypervariable regions, known as “complementarity determining regions” or “CDRs.” The CDRs are primarily responsible for binding to an epitope of an antigen. The framework regions of an antibody serve to position and align the CDRs in three-dimensional space. The amino acid sequence boundaries of a given CDR can be readily determined using any of a number of well-known numbering schemes, including those described by Kabat et al. (Sequences of Proteins of Immunological Interest, U.S. Department of Health and Human Services, 1991; the “Kabat” numbering scheme), Chothia et al. (see Chothia and Lesk, J Mol Biol 196:901-917, 1987; Chothia et al., Nature 342:877, 1989; and Al-Lazikani et al., JMB 273,927-948, 1997; the “Chothia” numbering scheme), Kunik et al. (see Kunik et al., PLoS Comput Biol 8:e1002388, 2012; and Kunik et al., Nucleic Acids Res 40(Web Server issue):W521-524, 2012; “Paratome CDRs”) and the ImMunoGeneTics (IMGT) database (see, Lefranc, Nucleic Acids Res 29:207-9, 2001; the “IMGT” numbering scheme). The Kabat, Paratome and IMGT databases are maintained online. In addition, the AbRSA tool can be used to determine the CDR boundaries according to Kabat, IMGT or Chothia (online at aligncdr.labshare.cn / aligncdr / abrsa.php). A “single-domain antibody” refers to an antibody having a single domain (a variable domain) that is capable of specifically binding an antigen, or an epitope of an antigen, in the absence of an additional antibody domain. Single-domain antibodies include, for example, VHdomain antibodies, VNAR antibodies, camelid VHH antibodies, and VL domain antibodies. VNAR antibodies are produced by cartilaginous fish, such as nurse sharks, wobbegong sharks, spiny dogfish and bamboo sharks. Camelid VHH antibodies are produced by several species including camel, llama, alpaca, dromedary, and guanaco, which produce heavy chain antibodies that are naturally devoid of light chains. A “monoclonal antibody” is an antibody produced by a single clone of lymphocytes or by a cell into which the coding sequence of a single antibody has been transfected. Monoclonal antibodies are produced by methods known to those of skill in the art. Monoclonal antibodies include humanized monoclonal antibodies. A “chimeric antibody” has framework residues from one species, such as human, and CDRs (which generally confer antigen binding) from another species (such as mouse). A “humanized” antibody is an immunoglobulin including a human framework region and one or more CDRs from a non-human (for example a mouse, rabbit, rat, shark or synthetic) immunoglobulin. The non-human immunoglobulin providing the CDRs is termed a “donor,” and the human immunoglobulin providing the framework is termed an “acceptor.” In one aspect, all CDRs are from the donor immunoglobulin in a humanized immunoglobulin. Constant regions need not be present, but if they are, they must be substantially identical to human immunoglobulin constant regions, such as at least about 85-90%, such as about 95% or more identical. Hence, all parts of a humanized immunoglobulin, except possibly the CDRs, are substantially identical to corresponding4239-111442-02parts of natural human immunoglobulin sequences. A humanized antibody binds to the same antigen as the donor antibody that provides the CDRs. Humanized or other monoclonal antibodies can have additional conservative amino acid substitutions which have substantially no effect on antigen binding or other immunoglobulin functions. Antibody-drug conjugate (ADC): A molecule that includes an antibody (or antigen-binding fragment of an antibody) conjugated to a drug, such as a cytotoxic agent. ADCs can be used to specifically target a drug to cancer cells through specific binding of the antibody to a tumor antigen expressed on the cell surface. Exemplary drugs for use with ADCs include anti-microtubule agents, such as maytansinoids, auristatin E (e.g., monomethyl auristatin E) and auristatin F, interstrand crosslinking agents (e.g., pyrrolobenzodiazepines; PDBs), and exatecan. Binding affinity: Affinity of an antibody for an antigen. In one aspect, affinity is calculated by a modification of the Scatchard method described by Frankel et al., Mol. Immunol., 16:101-106, 1979. In another aspect, binding affinity is measured by an antigen / antibody dissociation rate. In another aspect, a binding affinity is measured by a competition radioimmunoassay. In another aspect, binding affinity is measured by ELISA. In other aspects, antibody affinity is measured by flow cytometry, surface plasmon reference, or biolayer interferometry (BLI). An antibody that “specifically binds” an antigen (such as FGFR4) is an antibody that binds the antigen with high affinity and does not significantly bind other unrelated antigens. In some examples, a monoclonal antibody (such as an anti-FGFR4 antibody or ADC containing an anti-FGFR4 antibody provided herein) specifically binds to a target (such as a FGFR4) with a binding constant that is at least 103M-1greater, 104M-1greater or 105M-1greater than a binding constant for other molecules in a sample or subject. In some examples, an antibody (e.g., monoclonal antibody or ADAC) has an equilibrium constant (KD) of 5 µM or less, such as 5,000 nM or less, 900 nM or less, 500 nM or less, 250 nM or less, 100 nM or less, 50 nM or less, 10 nM or less, 5 nM or less, or 1 nM or less. For example, a monoclonal antibody binds to a target, such as FGFR4, with a binding affinity of at least about 1 x 10-6M, at least about 0.5 x 10-6M, at least about 1 x 10-7M, at least about 0.5 x 10-7M, at least about 1 x 10-8M, at least about 0.5 x 10-8M, at least about 1 x 10-9M, at least about 0.5 x 10-9M, or at least about 0.1 x 10-9. In certain aspects, a specific binding agent that binds to its target has a dissociation constant (Kd) of ≤1000 nM, ≤750 nM, 500 nM, ≤250 nM, ≤100 nM, ≤50 nM, ≤25 nM, ≤10 nM, ≤5 nM, ≤2.5 nM, ≤1 nM, ≤0.5 nM, ≤0.25 nM, ≤0.01 nM, or ≤0.001 nM (e.g., 10-6M or less, e.g., from 10-6M to 10-10M, e.g., from 10-10M to 10-12M). In some examples, binding affinity is measured using the Octet system (Creative Biolabs), which is based on BLI technology. In some examples, Kd is measured using surface plasmon resonance assays using a BIACORES-2000 or a BIACORES-3000 (BIAcore, Inc., Piscataway, N.J.). Breast cancer: A type of cancer that forms in tissues of the breast, usually the ducts and lobules. Types of breast cancer include, for example, ductal carcinoma in situ, invasive ductal carcinoma, triple negative breast cancer, inflammatory breast cancer, metastatic breast cancer,4239-111442-02medullary carcinoma, tubular carcinoma and mucinous carcinoma. Triple negative breast cancer refers to a type of breast cancer in which the cancer cells do not express estrogen receptors, progesterone receptors or significant levels of HER2 / neu protein. Triple negative breast cancer is also called ER-negative PR-negative HER2 / neu-negative breast cancer. Chemotherapeutic agent: Any chemical agent with therapeutic usefulness in the treatment of diseases characterized by abnormal cell growth. Such diseases include tumors, neoplasms, and cancer as well as diseases characterized by hyperplastic growth. In one aspect, a chemotherapeutic agent is an agent of use in treating a FGFR4-expressing tumor. In one aspect, a chemotherapeutic agent is a radioactive compound. A skilled person can readily identify a chemotherapeutic agent of use (see for example, Slapak and Kufe, Principles of Cancer Therapy, Chapter 86 in Harrison's Principles of Internal Medicine, 14th edition; Perry et al., Chemotherapy, Ch.17 in Abeloff, Clinical Oncology 2nded., © 2000 Churchill Livingstone, Inc; Baltzer, L., Berkery, R. (eds.): Oncology Pocket Guide to Chemotherapy, 2nd ed. St. Louis, Mosby-Year Book, 1995; Fischer, D.S., Knobf, M.F., Durivage, H.J. (eds): The Cancer Chemotherapy Handbook, 4th ed. St. Louis, Mosby-Year Book, 1993). Combination chemotherapy is the administration of more than one agent to treat cancer. One example is the administration of an antibody or ADC that binds FGFR4 used in combination with a radioactive or chemical compound. In one example, a chemotherapeutic agent is a biologic, such as a therapeutic antibody (e.g., therapeutic monoclonal antibody), such as anti-PD1 or anti-PDL1 (e.g., pembrolizumab and nivolumab), anti-CTLA4 (e.g., ipilimumab), anti-EGFR (e.g., cetuximab), anti- VEGF (e.g., bevacizumab), or combinations thereof (e.g., anti-PD-1 and anti-CTLA-4). Complementarity determining region (CDR): Amino acid sequences which together define the binding affinity and specificity of the natural Fv region of a native Ig binding site. The light and heavy chains of an Ig each have three CDRs, designated LCDR1, LCDR2, LCDR3 and HCDR1, HCDR2 and HCDR3, respectively. Conjugate: In the context of the present disclosure, a “conjugate” is an antibody or antibody fragment (such as an antigen-binding fragment) covalently linked to an effector molecule (such as an anti-cancer drug) or a second protein (such as a second antibody). The effector molecule can be, for example, a drug, toxin, therapeutic agent, detectable label, protein, nucleic acid, lipid, nanoparticle, photon absorber, carbohydrate or recombinant virus. When the conjugate includes an antibody linked to a drug (such as a cytotoxic agent), the conjugate is referred to as an “antibody-drug conjugate” or “ADC.” Other antibody conjugates include, for example, multi-specific (such as bispecific or trispecific) antibodies and chimeric antigen receptors (CARs). Similarly, the term “conjugated” refers to covalent linkage of one molecule (such as an antibody) to another molecule (such as a drug). Conservative variant: A protein containing conservative amino acid substitutions that do not substantially affect or decrease the activity or affinity of a protein, such as the affinity of an antibody to FGFR4. For example, a monoclonal antibody that specifically binds FGFR4 can include at most about 1, at most about 2, at most about 5, and most about 10, or at most about 15 conservative4239-111442-02substitutions and specifically bind the FGFR4 polypeptide. The term “conservative variant” also includes the use of a substituted amino acid in place of an unsubstituted parent amino acid, provided that antibody specifically binds FGFR4. Non-conservative substitutions are those that reduce an activity or binding to FGFR4. Conservative amino acid substitution tables providing functionally similar amino acids are well known. The following six groups are examples of amino acids that are considered to be conservative substitutions for one another: 1) Alanine (A), Serine (S), Threonine (T); 2) Aspartic acid (D), Glutamic acid (E); 3) Asparagine (N), Glutamine (Q); 4) Arginine (R), Lysine (K); 5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V); and 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W). Contacting: Placement in direct physical association; includes both in solid and liquid form. Desmoplastic small round cell tumor (DSRCT): A type of tumor that grows in the abdomen and pelvic area. DSRCT is typically a soft tissue sarcoma, which is a type of cancer that forms in the connective tissue of the body, such as fat, muscles, tendons, blood vessels and nerves. This type of cancer is rare and typically occurs in young white males between the ages of 10 and 30. Drug: Any compound used to treat, ameliorate or prevent a disease or condition in a subject. In some aspects herein, the drug is an anti-cancer agent, for example a cytotoxic agent, such as an anti-mitotic or anti-microtubule agent. In some aspects, the drug is MMAE or exatecan. Exatecan: A camptothecin analog that is a potent inhibitor of topoisomerase I. Exatecan inhibits topoisomerase I by stabilizing the cleavable complex between topoisomerase I and DNA and inhibiting relegation of DNA breaks, thereby inhibiting DNA replication and triggering apoptotic cell death. The molecular formula of exatecan is C24H22FN3O4. Fibroblast growth factor receptor (FGFR): A family of tyrosine kinase receptors activated by fibroblast growth factors (FGF), comprising extracellular immunoglobulin-like domains, a transmembrane domain, and an intracellular tyrosine kinase domain. The family includes at least four members: FGFR1, FGFR2, FGFR3, and FGFR4. FGFR4 is involved in the regulation of several pathways, including cell proliferation, cell differentiation, cell migration, lipid metabolism, bile acid biosynthesis, vitamin D metabolism, glucose uptake, and phosphate homeostasis. The FGFR4 protein is composed of an extracellular region having three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment, and a cytoplasmic tyrosine kinase domain. Exemplary sequences for FGFR4 are publicly available such as under NCBI Gene ID 2264. FGFR4-expressing cancer: Any type of cancer that expresses or overexpresses FGFR4. Exemplary FGFR4-expressing cancers include, but are not limited to, rhabdomyosarcoma (RMS; such as alveolar RMS or embryonal RMS), lung cancer, liver cancer (such as hepatocellular carcinoma or4239-111442-02hepatoblastoma), breast cancer, pancreatic cancer, prostate cancer, desmoplastic small round cell tumor, adrenocortical carcinoma, and gastric adenocarcinoma. Framework region: Amino acid sequences interposed between CDRs. Framework regions include variable light and variable heavy framework regions. The framework regions serve to hold the CDRs in an appropriate orientation for antigen binding. Gastric adenocarcinoma: An adenocarcinoma of the stomach (also known as stomach cancer). Gastric adenocarcinoma begins in the mucus-producing cells in the innermost lining of the stomach. Isolated: An “isolated” biological component, such as a nucleic acid, protein (including antibodies) or organelle, has been substantially separated or purified away from other biological components in the environment (such as a cell) in which the component naturally occurs, i.e., other chromosomal and extra-chromosomal DNA and RNA, proteins and organelles. Nucleic acids and proteins that have been “isolated” include nucleic acids and proteins purified by standard purification methods. The term also embraces nucleic acids and proteins prepared by recombinant expression in a host cell as well as chemically synthesized nucleic acids and proteins. Linker: In some cases, a linker is a peptide within an antibody binding fragment (such as an Fv fragment) which serves to indirectly bond the variable heavy chain to the variable light chain. “Linker” can also refer to a peptide serving to link a targeting moiety, such as an antibody, to an effector molecule, such as a drug or a detectable label. In some aspects herein, the linker connecting an FGFR4-specific antibody to a drug is mpGlyAsnAsn(Beta-Ala) or Valine-citruline-p- aminocarbamate (VC-PABC). The terms “conjugating,” “joining,” “bonding” or “linking” refer to making two polypeptides into one contiguous polypeptide molecule, or to covalently attaching a radionuclide, drug or other molecule to a polypeptide, such as an antibody or antibody fragment. In the specific context, the terms include reference to joining a ligand, such as an antibody moiety, to an effector molecule. The linkage can be either by chemical or recombinant means. “Chemical means” refers to a reaction between the antibody moiety and the effector molecule such that there is a covalent bond formed between the two molecules to form one molecule. Liver cancer: Any type of cancer occurring in liver tissue. The most common type of liver cancer is hepatocellular carcinoma (HCC), which develops in hepatocytes. Other types of liver cancer include cholangiocarcinoma, which develops in the bile ducts; liver angiosarcoma, which is a rare form of liver cancer that begins in the blood vessels of the liver; and hepatoblastoma (HBL), which is a very rare type of liver cancer found most often in children. Lung cancer: Cancer that forms in tissues of the lung, usually in the cells lining air passages. The two main types are small cell lung cancer and non-small cell lung cancer. These types can be diagnosed using microscopy.4239-111442-02Monomethyl auristatin E (MMAE): A potent anti-cancer drug. MMAE an antimitotic agent that inhibits cell division by blocking the polymerization of tubulin. Due to its strong toxicity, MMAE is not administered as a stand-alone treatment, but rather is linked to a tumor-targeted monoclonal antibody as part of an ADC. mpGlyAsnAsn(Beta-Ala), mpGlyAsnAsn, mpGlyAsnAsnGly and mpGlyAsnAsn(GABA): Legumain-cleavable linkers comprised of a maleimide propionyl spacer (“mp”) and the indicated amino acids (see Miller et al., Bioconjug Chem 32(4):842-858, 2021). Representative structures of ADCs including these linkers and exatecan are provided below: cells that results from excessive cell division. Neoplastic growth can produce a tumor. The amount of a tumor in an individual is the “tumor burden” which can be measured as the number, volume, or weight of the tumor. A tumor that does not metastasize is referred to as “benign.” A tumor that invades the surrounding tissue and / or can metastasize is referred to as “malignant.” Pancreatic cancer: A disease in which malignant cells are found in the tissues of the pancreas. Pancreatic tumors can be either exocrine tumors or neuroendocrine tumors, based on the cell origin of the cancer. The vast majority (~94%) of pancreatic cancers are exocrine tumors. Exocrine cancers include, for example, adenocarcinoma (the most common type of exocrine tumor), acinar cell carcinoma, intraductal papillary-mucinous neoplasm (IPMN), and mucinous cystadenocarcinoma. In some aspects, the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). Pancreatic neuroendocrine tumors, also referred to as islet cell tumors, are classified by the4239-111442-02type of hormones they produce. Exemplary neuroendocrine tumors include gastrinoma, glucaganoma, insulinoma, somatostatinoma, VIPoma (vasoactive intestinal peptide) and nonfunctional islet cell tumor. Pharmaceutically acceptable carriers: The pharmaceutically acceptable carriers of use are conventional. Remington: The Science and Practice of Pharmacy, The University of the Sciences in Philadelphia, Editor, Lippincott, Williams, & Wilkins, Philadelphia, PA, 21stEdition (2005), describes compositions and formulations suitable for pharmaceutical delivery of the ADCs and other compositions disclosed herein. In general, the nature of the carrier will depend on the particular mode of administration being employed. For instance, parenteral formulations usually comprise injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle. For solid compositions (such as powder, pill, tablet, or capsule forms), conventional non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate. In addition to biologically neutral carriers, pharmaceutical compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate. Preventing, treating or ameliorating a disease: “Preventing” a disease refers to inhibiting the full development of a disease. “Treating” refers to a therapeutic intervention that ameliorates a sign or symptom of a disease or pathological condition after it has begun to develop, such as a reduction in tumor burden or a decrease in the number of size of metastases. “Ameliorating” refers to the reduction in the number or severity of signs or symptoms of a disease, such as cancer. Prostate Cancer: A malignant tumor, generally of glandular origin, of the prostate. Prostate cancers include adenocarcinomas and small cell carcinomas. Many prostate cancers express prostate specific antigen (PSA). Rhabdomyosarcoma (RMS): A soft tissue malignant tumor of skeletal muscle origin. The most common primary sites for rhabdomyosarcoma are the head and neck (e.g., parameningeal, orbit, pharyngeal, etc.), the genitourinary tract, and the extremities. Other less common primary sites include the trunk, chest wall, the abdomen (including the retroperitoneum and biliary tract), and the perineal / anal region. There are at least two types of RMS; the most common forms are alveolar RMS (ARMS) and embryonal histological RMS (ERMS). Approximately 20% of children with rhabdomyosarcoma have the ARMS subtype. An increased frequency of this subtype is noted in adolescents and in patients with primary sites involving the extremities, trunk, and perineum / perianal region. ARMS is associated with chromosomal translocations encoding a fusion gene involving FKHR on chromosome 13 and members of the PAX family. The embryonal subtype is the most frequently observed subtype in children, accounting for approximately 60-70% of rhabdomyosarcomas of childhood. Tumors with embryonal histology typically arise in the head and4239-111442-02neck region or in the genitourinary tract, although they may occur at any primary site. ERMS is characterized by a younger age at diagnosis, loss of heterozygosity, and altered genomic imprinting. Sequence identity: The similarity between amino acid or nucleic acid sequences is expressed in terms of the similarity between the sequences, otherwise referred to as sequence identity. Sequence identity is frequently measured in terms of percentage identity (or similarity or homology); the higher the percentage, the more similar the two sequences are. Homologs or variants of a polypeptide or nucleic acid molecule will possess a relatively high degree of sequence identity when aligned using standard methods. Methods of alignment of sequences for comparison are well-known. Various programs and alignment algorithms are described in: Smith and Waterman, Adv. Appl. Math.2:482, 1981; Needleman and Wunsch, J. Mol. Biol.48:443, 1970; Pearson and Lipman, Proc. Natl. Acad. Sci. U.S.A. 85:2444, 1988; Higgins and Sharp, Gene 73:237, 1988; Higgins and Sharp, CABIOS 5:151, 1989; Corpet et al., Nucleic Acids Research 16:10881, 1988; and Pearson and Lipman, Proc. Natl. Acad. Sci. U.S.A. 85:2444, 1988. Altschul et al., Nature Genet.6:119, 1994, presents a detailed consideration of sequence alignment methods and homology calculations. The NCBI Basic Local Alignment Search Tool (BLAST) (Altschul et al., J. Mol. Biol.215:403, 1990) is available from several sources, including the National Center for Biotechnology Information (NCBI, Bethesda, MD) and on the internet, for use in connection with the sequence analysis programs blastp, blastn, blastx, tblastn and tblastx. A description of how to determine sequence identity using this program is available on the NCBI website on the internet. Homologs and variants of a VL or a VH of an antibody that specifically binds FGFR4 or a fragment thereof are typically characterized by possession of at least about 75%, for example at least about 80%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity counted over the full length alignment with the amino acid sequence of the antibody using the NCBI Blast 2.0, gapped blastp set to default parameters. For comparisons of amino acid sequences of greater than about 30 amino acids, the Blast 2 sequences function is employed using the default BLOSUM62 matrix set to default parameters, (gap existence cost of 11, and a per residue gap cost of 1). When aligning short peptides (fewer than around 30 amino acids), the alignment should be performed using the Blast 2 sequences function, employing the PAM30 matrix set to default parameters (open gap 9, extension gap 1 penalties). Proteins with even greater similarity to the reference sequences will show increasing percentage identities when assessed by this method, such as at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity. When less than the entire sequence is being compared for sequence identity, homologs and variants will typically possess at least 80% sequence identity over short windows of 10-20 amino acids, and may possess sequence identities of at least 85% or at least 90% or 95% depending on their similarity to the reference sequence. Methods for determining sequence identity over such short windows are available at the NCBI website on the internet. A skilled4239-111442-02person will appreciate that these sequence identity ranges are provided for guidance only; it is entirely possible that strongly significant homologs could be obtained that fall outside of the ranges provided. Subject: Living multi-cellular vertebrate organisms, a category that includes both human and veterinary subjects, including human and non-human mammals. In some aspects, a subject is a human with an FGFR4-expressing cancer. Therapeutically effective amount: A quantity of a specific substance sufficient to achieve a desired effect in a subject being treated. For instance, this can be the amount of an ADC necessary to inhibit or suppress growth of a tumor. In one aspect, a therapeutically effective amount is the amount necessary to eliminate, reduce the size, or prevent metastasis of a tumor (such as an FGFR4- expressing cancer), such as reduce a tumor size and / or volume by at least 10%, at least 20%, at least 50%, at least 75%, at least 80%, at least 90%, at least 95%, or even 100%, and / or reduce the number and / or size / volume of metastases by at least 10%, at least 20%, at least 50%, at least 75%, at least 80%, at least 90%, at least 95%, or even 100%, for example as compared to a size / volume / number prior to treatment. In one aspect, a therapeutically effective amount is the amount necessary to increase the survival time of a subject with a tumor (such as an FGFR4-expressing cancer), such as increase survival time by at least 10%, at least 20%, at least 50%, at least 75%, at least 80%, at least 90%, at least 100%, at least 200%, at least 300%, at least 400%, or at least 500%, for example as compared to a survival time compared to a subject with no treatment or a different treatment. In one aspect, a therapeutically effective amount is the amount necessary to increase the survival time of a subject with a tumor (such as an FGFR4-expressing cancer), such as increase survival time by at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 18 months, at least 24 months, at least 36 months, at least 48 months, or at least 60 months, for example as compared a survival time compared to a subject with no treatment or a different treatment. In some aspects, combinations of these affects are achieved. When administered to a subject, a dosage will generally be used that will achieve target tissue concentrations (for example, in tumors) that has been shown to achieve a desired in vitro effect. Valine-citruline-p-aminocarbamate (VC-PABC): A linker comprised of a valine-citrulline (VC) dipeptide attached to p-aminocarbamate (PABC). VC-PABC is lysosomal protease-cleavable at the amide bonding linking citrulline to PABC. In the lysosomes, cleavage is mediated by one or more cathepsins, such as cathepsin B, S, L and / or F (Balamkundu and Liu, Biomedicines 11:3080, 2023). In some aspects, the linker includes mc-Val-Cit-PABC. The maleimidocaproyl (mc) group can be conjugated to thiols of an antibody. Mc-Val-Cit-PABC is commercially available from a variety of sources, such as MedChemExpress. IV. Anti-FGFR4 Monoclonal Antibody 3A11 The present disclosure describes highly potent antibody-drug conjugates (ADCs) targeting FGFR4. The ADCs include the FGFR4-specific monoclonal antibody 3A11 or antigen-binding4239-111442-02fragment(s) thereof. In some aspects, the ADC includes the VH and VL domains of antibody 3A11, which is a murine antibody. In other aspects, the ADC includes the VH and VL domains of a humanized version of 3A11. In other aspects, the ADC includes a chimeric version of antibody 3A11 (c3A11), which contains both murine and human sequences. In the context of the present disclosure, “3A11” refers to the original mouse 3A11 antibody; “c3A11” refers to a chimeric version of the antibody that includes the murine VH and VL domains and human constant regions; and “h3A11” refers to humanized versions of the 3A11 antibody that include a humanized VH domain and a humanized VL domain, and may optionally include one or more human constant regions. Provided below are the amino acid sequences of the VH and VL domains of murine antibody 3A11, and three humanized versions of 3A11 (h3A11-1, h3A11-2 and h3A11-3). The CDR sequences, as determined by IMGT, are also provided in Table 1 and are indicated in bold in the VH and VL domain sequences. VH domain of 3A11 (SEQ ID NO: 1) QVQLEQSGAELVRPGASVTLSCKASGYTFTDYEMHWVKQTPVHGLEWIGAIDPETGGTAY NQKFKGKAILTADKSSSTAYMELRSLTSEDSAVYYCTRGNYYGSDYDYWGQGTTLTVSS VL of 3A11 (SEQ ID NO: 2) DVVMTQTPLTLSVTIGQPASISCKSSQSLLDSDGETYLNWLLKRPGQSPKRLIYLVSKLDSGV PDRFTGSGSGTDFTLKISRVEAEDLGVYYCWQGTHFPQTFGGGTKLEIK Table 1. CDR sequences of antibody 3A11 (IMGT) CDR Sequence SEQ ID NO: h3A11-1 VH domain (SEQ ID NO: 9) QVQLQQSGAEVKKPGSSVKVSCKASGYTFTDYEISWVRQAPGQGLEWMGGIDPETGGTNY AQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTRGNYYGSDYDYWWGQGTMVTVSS4239-111442-02h3A11-1 VL domain (SEQ ID NO: 10) EIVLTQSPATLSLSPGERATLSCRASQSLLDSDAWYQQKPGQAPRLLIYLVSRATGIPARFSGS GSGTDFTLTISSLEPEDFAVYYCWQGTHFPQTFFGQGTKLEIK h3A11-2 VH domain (SEQ ID NO: 11) QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYEMHWVRQAPGQGLEWMGAIDPETGGT AYNQKFKGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARGNYYGSDYDYWGQGTLVTV SS h3A11-2 VL domain (SEQ ID NO: 12) DVVMTQSPLSLPVTLGQPASISCKSSQSLLDSDGETYLNWFQQRPGQSPRRLIYLVSKLDSGV PDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHFPQTFGGGTKVEIK h3A11-3 VH domain (SEQ ID NO: 13) QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYEMHWVRQAPGQGLEWMGAIDPETGGT AYNQKFKGRVTLTADKSTSTAYMELRSLTSEDTAVYYCARGNYYGSDYDYWGQGTLVTVS S h3A11-3 VL domain (SEQ ID NO: 14) DVVMTQSPLSLPVTPGQPASISCKSSQSLLDSDGETYLNWFQQRPGQSPRRLIYLVSKLDSGV PDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHFPQTFGQGTKVEIK As shown above, the VH domains of h3A11-2 and h3A11-3 have a single amino acid substitution in HCDR3 (T to A at position 97). Thus, an alternative HCDR3 sequence is set forth herein as CARGNYYGSDYDYW (SEQ ID NO: 19). Provided below are scFv sequences for 3A11 and humanized 3A11 (h3A11-1). The VH and VL domains are separated by a linker sequence, which is indicated by italic font. The CDR sequences are in bold font. 3A11 scFv (SEQ ID NO: 15) QVQLEQSGAELVRPGASVTLSCKASGYTFTDYEMHWVKQTPVHGLEWIGAIDPETGGTAY NQKFKGKAILTADKSSSTAYMELRSLTSEDSAVYYCTRGNYYGSDYDYWGQGTTLTVSSG GGGSGGGGSGGGGSDVVMTQTPLTLSVTIGQPASISCKSSQSLLDSDGETYLNWLLKRPGQS PKRLIYLVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGVYYCWQGTHFPQTFGGGTKLE IK4239-111442-02h3A11 scFv (SEQ ID NO: 16) QVQLQQSGAEVKKPGSSVKVSCKASGYTFTDYEISWVRQAPGQGLEWMGGIDPETGGTNY AQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTRGNYYGSDYDYWWGQGTMVTVSS GGGGSGGGGSGGGGSEIVLTQSPATLSLSPGERATLSCRASQSLLDSDAWYQQKPGQAPRLLI YLVSRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCWQGTHFPQTFFGQGTKLEIK Provided below are amino acid sequences of a heavy chain constant region and a light chain constant region from human IgG1. IgG1 heavy chain constant region (SEQ ID NO: 17) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK IgG1 light chain constant region (SEQ ID NO: 18) RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC V. FGFR4-Specific Antibody-Drug Conjugates (ADCs) Provided herein are antibody-drug conjugates (ADCs) that include a monoclonal antibody or antigen-binding domain thereof that specifically binds fibroblast growth factor receptor 4 (FGFR4), and a drug conjugated to the antibody or antigen-binding fragment. The monoclonal antibody or antigen-binding fragment includes a variable heavy (VH) domain and a variable light (VL) domain, wherein the VH domain includes the heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 sequences of the VH domain of antibody 3A11 (SEQ ID NO: 1) or h3A11- 2 / h3A11-3 (SEQ ID NO: 11 / SEQ ID NO: 13) and the VL domain includes the light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3 sequences of the VL domain of antibody 3A11 (SEQ ID NO: 2). In some aspects, the drug includes monomethyl auristatin E (MMAE). In other aspects, the drug includes exatecan or an exatecan derivative. In some aspects, the amino acid sequences of the HCDR1, HCDR2 and HCDR3 are set forth as SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5, respectively. In other aspects, the HCDR1, HCDR2 and HCDR3 are set forth as SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 19, respectively. In some aspects, the amino acid sequences of the LCDR1, LCDR2 and LCDR3 are set forth as SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8, respectively. In some examples, the4239-111442-02amino acid sequences of the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 are respectively set forth as SEQ ID NOs: 3-8, which were determined by IMGT. In other examples, the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 are respectively set forth as SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 19, SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8, in accordance with IMGT. In alternative aspects, the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 sequences are determined using a different numbering convention, such as Kabat or Chothia, or a combination of any two of IMGT, Kabat and Chothia. In some aspects, the amino acid sequence of the VH domain is at least 80%, at least 85%, about 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to SEQ ID NO: 1 and includes the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 1 or SEQ ID NO: 11; and / or the amino acid sequence of VL domain is at least 80%, at least 85%, about 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to SEQ ID NO: 2 and includes the LCDR1, LCDR2 and LCDR sequences of SEQ ID NO: 2. In some aspects, the amino acid sequence of the VH domain includes or consists of SEQ ID NO: 1; and / or the amino acid sequence of the VL domain includes or consists of SEQ ID NO: 2. In some aspects of the ADC, the VH domain and / or the VL domain are humanized. In some examples, the amino acid sequence of the VH domain is at least 80%, at least 85%, about 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to SEQ ID NO: 9 (h3A11- 1), SEQ ID NO: 11 (h3A11-2) or SEQ ID NO: 13 (h3A11-3); and / or the amino acid sequence of the VL domain is at least 80%, at least 85%, about 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to SEQ ID NO: 10 (h3A11-1), SEQ ID NO: 12 (h3A11-2) or SEQ ID NO: 14 (h3A11-3). In some aspects, the amino acid sequence of the VH domain includes or consists of SEQ ID NO: 9, SEQ ID NO: 11 or SEQ ID NO: 13; and / or the amino acid sequence of the VL domain includes or consists of SEQ ID NO: 10, SEQ ID NO: 12 or SEQ ID NO: 14. In some aspects of the ADC, the antigen-binding portion is an antigen-binding fragment of 3A11 or a humanized version thereof. In some aspects, the antigen-binding fragment is a single-chain variable fragment (scFv). In some examples, the amino acid sequence of the scFv is at least 80%, at least 85%, about 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to SEQ ID NO: 15 (3A11 scFv) or SEQ ID NO: 16 (h3A11 scFv). In particular examples, the amino acid sequence of the scFv includes or consists of SEQ ID NO: 15 or SEQ ID NO: 16. In other aspects of the ADC, the monoclonal antibody or antigen-binding fragment includes at least one constant domain. In some examples, the monoclonal antibody or antigen-binding fragment includes an scFv and an Fc region, such as a CH2 domain and a CH3 domain, for example a human CH2 domain and a human CH3 domain (scFvFc format), such as from IgG1 (e.g., human IgG1). In some examples, the monoclonal antibody or antigen-binding fragment includes a human heavy chain constant region (CH1, CH2 and CH3 domain). In specific examples, the amino acid sequence of the4239-111442-02constant region is at least 80%, at least 85%, about 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to SEQ ID NO: 17. In one non-limiting example, the amino acid sequence of the human heavy chain constant region includes or consists of SEQ ID NO: 17. In some aspects, the ADC includes or further includes a human light chain constant (LC) domain, such as a human IgG1 LC domain. In some examples, the amino acid sequence of the LC domain is at least 80%, at least 85%, about 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to SEQ ID NO: 18. In specific examples, the amino acid sequence of the LC domain includes or consists of SEQ ID NO: 18. In some aspects of the ADC, the drug is MMAE and MMAE is conjugated to the monoclonal antibody or antigen-binding fragment via a linker that includes valine-citruline-p-aminocarbamate (VC-PABC). In other aspects of the ADC, the drug is exatecan or an exatecan derivative. In some examples, the exatecan is conjugated to the monoclonal antibody or antigen-binding fragment via a linker that includes mpGlyAsnAsn, mpGlyAsnAsnGly, mpGlyAsnAsn(beta-Ala), or mpGlyAsnAsn(GABA). Representative structures of these linkers conjugated to exatecan are provided below, illustrating the putative released exatecan derivative for each:

[0002] 4239-111442-02 following structure: wherein X1 = bond or glycine; and X2 = bond, CH2, CH2CH2, or CH2CH2CH2.4239-111442-02Also provided are compositions that include an ADC disclosed herein and a pharmaceutically acceptable carrier. ADC compositions are discussed further in section VI. Further provided are methods of treating a FGFR4-expressing cancer in a subject. In some aspects, the method includes administering to the subject a therapeutically effective amount of an ADC or composition disclosed herein. Also provided are methods of inhibiting tumor growth or metastasis of a FGFR4-expressing cancer in a subject. In some aspects, the method includes administering to the subject a therapeutically effective amount of an ADC or composition disclosed herein. In some aspects of the methods, the FGFR4-expressing cancer is a rhabdomyosarcoma (RMS), a lung cancer, a liver cancer, a breast cancer, a pancreatic cancer, a prostate cancer, a desmoplastic small round cell tumor (DSRCT), an adrenocortical carcinoma (ACC), or a gastric adenocarcinoma. In some examples, the RMS is alveolar RMS (ARMS) or embryonal RMS (ERMS). In some examples, the liver cancer is hepatocellular carcinoma (HCC) or hepatoblastoma (HBL). In some aspects of the methods, the ADC is administered intravenously. In some aspects, the subject is a human subject. In other aspects, the subject is a non-human primate. In some aspects of the methods, the subject is administered multiple doses of the ADC, such as two, three, four, five, six, seven or eight doses of the ADC. In some aspects, the method includes administering to the subject an additional anti-cancer agent; performing surgery on the subject to resect a tumor; and / or subjecting the subject to radiation therapy. Methods of using the disclosed ADCs and compositions disclosed herein are further described in section VII. VI. ADC Compositions Compositions are provided that include an FGFR4-targeted ADC in a pharmaceutically acceptable carrier. The compositions can be prepared in unit dosage forms for administration to a subject. The amount and timing of administration are at the discretion of the treating clinician to achieve the desired outcome. The ADC or composition can be formulated for systemic or local (such as intra-tumor) administration. In some aspects, the antibody is formulated for parenteral administration, such as intravenous administration. The compositions for administration can include a solution of the ADC in a pharmaceutically acceptable carrier, such as an aqueous carrier. A variety of aqueous carriers can be used, for example, buffered saline and the like. These solutions are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional sterilization techniques. The compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents and the like, for4239-111442-02example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of antibody in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight and the like in accordance with the particular mode of administration selected and the subject’s needs. The compositions that include an ADC can be formulated in unit dosage form suitable for individual administration of precise dosages. In addition, the compositions may be administered in a single dose or in a multiple dose schedule. A multiple dose schedule is one in which a primary course of treatment may be with more than one separate dose, for instance 1-10 doses, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 doses, followed by other doses given at subsequent time intervals as needed to maintain or reinforce the action of the compositions. Treatment can involve daily or multi-daily doses of compound(s) over a period of a few days to months, or even years. Thus, the dosage regime can also, at least in part, be determined based on the particular needs of the subject to be treated and can be dependent upon the judgment of the administering practitioner. Typical dosages of the ADCs, compositions or additional agents can range from about 0.01 to about 30 mg / kg, such as from about 0.1 to about 10 mg / kg. In some examples, the dosage is at least about 0.1 mg / kg, at least about 0.2 mg / kg, at least about 0.3 mg / kg, at least about 0.4 mg / kg, at least about 0.5 mg / kg, at least about 1 mg / kg, at least about 4 mg / kg, at least about 3 mg / kg, at least about 5 mg / kg, at least about 6 mg / kg, at least about 7 mg / kg, at least about 8 mg / kg is at least about 9 mg / kg, at least about 10 mg / kg, at least about 11 mg / kg, at least about 12 mg / kg, at least about 13 mg / kg, at least about 14 mg / kg, at least about 15 mg / kg, at least about 16 mg / kg, at least about 17 mg / kg, at least about 18 mg / kg, at least about 19 mg / kg, at least about 20 mg / kg, at least about 21 mg / kg, at least about 22 mg / kg, at least about 23 mg / kg, at least about 24 mg / kg at least about 25 mg / kg, at least about 26 mg / kg, at least about 27 mg / kg, at least about 28 mg / kg, at least about 29 mg / kg, or at least about 30 mg / kg. In particular examples, the subject is administered an ADC or composition thereof, or additional agent(s), on a multiple daily dosing schedule, such as at least two consecutive days, 10 consecutive days, and so forth, for example for a period of weeks, months, or years. In one example, the subject is administered the ADC, composition or additional agent(s) for a period of at least 30 days, such as at least 2 months, at least 4 months, at least 6 months, at least 12 months, at least 24 months, or at least 36 months. In some aspects, a disclosed ADC or composition is administered intravenously, subcutaneously or by another mode daily or multiple times per week for a period of time, followed by a period of no treatment, then the cycle is repeated. In some aspects, the initial period of treatment (e.g., administration of the therapeutic agent daily or multiple times per week) is for 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks or 12 weeks. In a related aspect, the period of no treatment lasts for 3 days, 1 week, 2 weeks, 3 weeks or 4 weeks. In certain aspects, the dosing regimen of the therapeutic agent is daily for 3 days followed by4239-111442-023 days off; or daily or multiple times per week for 1 week followed by 3 days or 1 week off; or daily or multiple times per week for 2 weeks followed by 1 or 2 weeks off; or daily or multiple times per week for 3 weeks followed by 1, 2 or 3 weeks off; or daily or multiple times per week for 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks followed by 1, 2, 3 or 4 weeks off. The ADCs disclosed herein can also be administered by other routes, including via inhalation, oral, topical or intratumoral. In some examples, the ADC is administered via a fine-needle. ADCs may be provided in lyophilized form and rehydrated with sterile water before administration, although they are also provided in sterile solutions of known concentration. The ADC solution is then added to an infusion bag containing 0.9% sodium chloride, USP, and in some cases administered at a dosage of from 0.5 to 15 mg / kg of body weight. Considerable experience is available in the art in the administration of antibody drugs, which have been marketed in the U.S. since the approval of RITUXANTMin 1997. ADCs can be administered by slow infusion, rather than in an intravenous push or bolus. In one example, a higher loading dose is administered, with subsequent, maintenance doses being administered at a lower level. Controlled release parenteral formulations can be made as implants, oily injections, or as particulate systems. For a broad overview of protein delivery systems see, Banga, A.J., Therapeutic Peptides and Proteins: Formulation, Processing, and Delivery Systems, Technomic Publishing Company, Inc., Lancaster, PA, (1995). Particulate systems include, for example, microspheres, microparticles, microcapsules, nanocapsules, nanospheres, and nanoparticles. Microcapsules contain the therapeutic protein, such as a cytotoxin or a drug, as a central core. In microspheres the therapeutic is dispersed throughout the particle. Particles, microspheres, and microcapsules smaller than about 1 µm are generally referred to as nanoparticles, nanospheres, and nanocapsules, respectively. Capillaries have a diameter of approximately 5 µm so that only nanoparticles are administered intravenously. Microparticles are typically around 100 µm in diameter and are administered subcutaneously or intramuscularly. See, for example, Kreuter, J., Colloidal Drug Delivery Systems, J. Kreuter, ed., Marcel Dekker, Inc., New York, NY, pp.219-342 (1994); and Tice & Tabibi, Treatise on Controlled Drug Delivery, A. Kydonieus, ed., Marcel Dekker, Inc. New York, NY, pp.315-339, (1992). Polymers can be used for ion-controlled release of the ADC compositions disclosed herein. Various degradable and nondegradable polymeric matrices for use in controlled drug delivery are known (e.g., see Langer, Accounts Chem. Res.26:537-542, 1993). For example, the block copolymer, polaxamer 407, exists as a viscous yet mobile liquid at low temperatures but forms a semisolid gel at body temperature. Alternatively, hydroxyapatite has been used as a microcarrier for controlled release of proteins such as ADCs (Ijntema et al., Int. J. Pharm.112:215-224, 1994). In yet another aspect, liposomes are used for controlled release as well as drug targeting of the lipid-capsulated drug (Betageri et al., Liposome Drug Delivery Systems, Technomic Publishing Co., Inc., Lancaster, PA4239-111442-02(1993)). Numerous additional systems for controlled delivery of therapeutic proteins such as ADCs are known (see U.S. Patent Nos.5,055,303; 5,188,837; 4,235,871; 4,501,728; 4,837,028; 4,957,735; 5,019,369; 5,055,303; 5,514,670; 5,413,797; 5,268,164; 5,004,697; 4,902,505; 5,506,206; 5,271,961; 5,254,342 and 5,534,496). VII. Methods of Use The ADCs disclosed herein can be administered to slow or inhibit the growth of tumor cells, inhibit the metastasis of tumor cells, and / or increase the survival of a subject having a tumor, such as an FGFR4-expressing tumor, such as solid tumors. In these applications, a therapeutically effective amount of a composition is administered to a subject in an amount sufficient to inhibit growth, replication or metastasis of cancer cells, increase the survival of a subject having a tumor, and / or to inhibit a sign or a symptom of the cancer. Suitable subjects may include those diagnosed with a cancer that expresses FGFR4, such as, but not limited to RMS (e.g., ARMS or ERMS), a lung cancer, a liver cancer (e.g., HCC or HBL), a breast cancer, a pancreatic cancer, a prostate cancer, desmoplastic small round cell tumor (DSRCT), an adrenocortical carcinoma (ACC), or a gastric adenocarcinoma. Provided herein is a method of treating a FGFR4-expressing cancer in a subject by administering to the subject a therapeutically effective amount of an ADC or composition disclosed herein. Also provided herein is a method of inhibiting tumor growth or metastasis of a FGFR4- expressing cancer in a subject by administering to the subject a therapeutically effective amount of an ADC or composition disclosed herein. In some aspects, the FGFR4-expressing cancer is RMS (e.g., ARMS or ERMS), a lung cancer, a liver cancer (e.g., HCC or HBL), a breast cancer, a pancreatic cancer, a prostate cancer, DSRCT, ACC, or a gastric adenocarcinoma. A therapeutically effective amount of a FGFR4-specific ADC or composition disclosed herein can depend upon the severity of the disease, the type of disease, and the general state of the patient’s health. A therapeutically effective amount of the antibody-based composition is that which provides either subjective relief of a symptom(s) or an objectively identifiable improvement as noted by the clinician or other qualified observer. Administration of the FGFR4-specific ADCs and compositions disclosed herein can also be accompanied by administration of other anti-cancer agents or therapeutic treatments (such as surgical resection of a tumor). Any suitable anti-cancer agent can be administered in combination with the ADCs and compositions disclosed herein. Exemplary anti-cancer agents include, but are not limited to, chemotherapeutic agents, such as, for example, mitotic inhibitors, alkylating agents, anti- metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, anti-survival agents, biological response modifiers, anti-hormones (e.g. anti- androgens) and anti-angiogenesis agents. Other anti-cancer treatments include radiation therapy and other antibodies that specifically target cancer cells.4239-111442-02Non-limiting examples of alkylating agents include nitrogen mustards (such as mechlorethamine, cyclophosphamide, melphalan, uracil mustard or chlorambucil), alkyl sulfonates (such as busulfan), nitrosoureas (such as carmustine, lomustine, semustine, streptozocin, or dacarbazine). Non-limiting examples of antimetabolites include folic acid analogs (such as methotrexate), pyrimidine analogs (such as 5-FU or cytarabine), and purine analogs, such as mercaptopurine or thioguanine. Non-limiting examples of natural products include vinca alkaloids (such as vinblastine, vincristine, or vindesine), epipodophyllotoxins (such as etoposide or teniposide), antibiotics (such as dactinomycin, daunorubicin, doxorubicin, bleomycin, plicamycin, or mitomycin C), and enzymes (such as L-asparaginase). Non-limiting examples of miscellaneous agents include platinum coordination complexes (such as cis-diamine-dichloroplatinum II also known as cisplatin), substituted ureas (such as hydroxyurea), methyl hydrazine derivatives (such as procarbazine), and adrenocrotical suppressants (such as mitotane and aminoglutethimide). Non-limiting examples of hormones and antagonists include adrenocorticosteroids (such as prednisone), progestins (such as hydroxyprogesterone caproate, medroxyprogesterone acetate, and magestrol acetate), estrogens (such as diethylstilbestrol and ethinyl estradiol), antiestrogens (such as tamoxifen), and androgens (such as testerone proprionate and fluoxymesterone). Examples of the most commonly used chemotherapy drugs include Adriamycin, Alkeran, Ara-C, BiCNU, Busulfan, CCNU, Carboplatinum, Cisplatinum, Cytoxan, Daunorubicin, DTIC, 5-FU, Fludarabine, Hydrea, Idarubicin, Ifosfamide, Methotrexate, Mithramycin, Mitomycin, Mitoxantrone, Nitrogen Mustard, Taxol (or other taxanes, such as docetaxel), Velban, Vincristine, VP-16, while some more newer drugs include Gemcitabine (Gemzar), Herceptin, Irinotecan (Camptosar, CPT-11), Leustatin, Navelbine, Rituxan STI-571, Taxotere, Topotecan (Hycamtin), Xeloda (Capecitabine), Zevelin and calcitriol. Non-limiting examples of immunomodulators that can be used include AS-101 (Wyeth- Ayerst Labs.), bropirimine (Upjohn), gamma interferon (Genentech), GM-CSF (granulocyte macrophage colony stimulating factor; Genetics Institute), IL-2 (Cetus or Hoffman-LaRoche), human immune globulin (Cutter Biological), IMREG (from Imreg of New Orleans, La.), SK&F 106528, and TNF (tumor necrosis factor; Genentech). Another common treatment for some types of cancer is surgical treatment, for example surgical resection of the cancer or a portion of it. Another example of a treatment is radiotherapy, for example administration of radioactive material or energy (such as external beam therapy) to the tumor site to help eradicate the tumor or shrink it prior to surgical resection.4239-111442-02EXAMPLES The following examples are provided to illustrate particular features of certain aspects of the disclosure, but the scope of the claims should not be limited to those features exemplified. Example 1: Preparation of 3A11-mcValCitPABC-MMAE The 3A11 anti-FGFR4 antibody (7.5 mg, 637 µL of a 11.77 mg / mL stock solution) was added to 2708 µL of DPBS containing 5 mM EDTA. Tris(2-carboxyethyl)phosphine (TCEP) (30 µL of 5 mM stock, 3 molar equivalents) was added to the solution and the antibody was incubated at 37°C for 1.5 hours. mcValCitPABC-MMAE (purchased from MedChemExpress, HY-15575) (80 µL of a 5 mM stock; 8 eq.) was pre-mixed with 295 µL of DMSO and added to the reduced antibody. After incubating at room temperature for 3 hours, the product was buffer-exchanged into DPBS using 2.5 mL PD-10 desalting columns packed with Sephadex G-25 resin (Cytiva). The material was concentrated as needed through a 30 kd spin column. The final product was filter sterilized through a 0.2 µm filter. A second batch was conjugated via the same method and the two batches were mixed for final characterization. The drug-antibody ratio (DAR) was measured via HPLC-MS and aggregation percentage was measured via SEC. Approximately 13.6 mg of the final 3A11- mcValCitPABC-MMAE was obtained from 15 mg of anti-FGFR4 antibody. The calculated DAR was 3.0 (FIG.1A) and no significant aggregation was observed (FIG.1B). Example 2: Preparation of anti-HEL-mcValCitPABC-MMAE The anti-hen egg lysozyme (HEL) human IgG1-kappa antibody (abinvivo, B117901) (7.5 mg, 540 µL of a 13.90 mg / mL stock solution) was added to 2715 µL of DPBS containing 5 mM EDTA. Tris(2-carboxyethyl)phosphine (TCEP) (45 µL of 5 mM stock, 4.5 molar equivalents) was added to the solution and the antibody was incubated at 37°C for 1.5 hours. ValCitPABC-MMAE (95 µL of a 5 mM stock; 9.5 eq.) was pre-mixed with 280 µL of DMSO and added to the reduced antibody. After incubating at room temperature for 3 hours, the product was buffer-exchanged into DPBS using 2.5 mL PD-10 desalting columns packed with Sephadex G-25 resin (Cytiva). The material was concentrated as needed through a 30 kd spin column. The final product was filter sterilized through a 0.2 µm filter. A second batch was conjugated via the same method and the two batches were mixed for final characterization. The DAR was measured via HPLC-MS and aggregation percentage was measured via SEC. Approximately 13.2 mg of the final anti-HE-mcValCitPABC-MMAE (2.20 mg / mL, 6 mL) was obtained from 15 mg of anti-FGFR4 antibody. The calculated DAR was 3.8 (FIG. 2A) and no significant aggregation was observed (FIG.2B).4239-111442-02Example 3: Synthesis of mpAsnAsn-Extecan (S)-N1-((S)-4-amino-1-(((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo- 2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)- 1,4-dioxobutan-2-yl)-2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)succinimide 1.5 Eq, 46.0 μmol) were dissolved in 2.8 mL dry DMF and treated with PYBOP (24.0 mg, 1.5 Eq, 46.0 μmol) and diisopropylethylamine (9.92 mg, 13.3 μL, 2.5 Eq, 76.7 μmol). The reaction was stirred for 15 mins at room temperature and was monitored by TLC and UPLC. Upon completion, the solvent was removed. LCMS rt = 3.82 min; m / z = 1370.8 [M+H]. Step 2. The crude product of step 1 was dissolved in DMF (0.16 mL) and treated with piperidine (.04 mL, 1 Eq). After 10 min, the solvent was evaporated. LCMS rt = 3.52 min; m / z = 1148.6 [M+H]. Step 3. The crude product of step 2 (~20 mg) was dissolved in DMF (0.35 mL) and mpOSu (9.3 mg, 2 Eq, 35 µmol) was added at room temperature and stirred for 2 hours. The reaction was monitored by TLC and UPLC. The solvent was removed and the crude product was used without further purification. LCMS rt = 3.51 min; m / z = 1301.0 [M+H]. Step 4. The material of step 3 was dissolved into 250 µl of DCM and treated with 5 mL of TFA:TES:H2O (95:2.5:2.5). After 30 seconds, the reaction was concentrated to dryness and the solid was redissolved in 0.75 mL DMF for purification by preparative HPLC providing the title compound. LCMS rt = 2.30 min; m / z = 815.4 [M+H]; HPLC Purity = 97%; Overall yield = 54.2%.1H NMR (400 MHz, DMSO) δH / ppm 8.34 – 8.11 (m, 3H), 7.73 (dd, J = 5.89 Hz, 11.31 Hz, 1H), 7.29 (d, J = 3.67 Hz, 1H), 7.26 (bs, 1H), 6.96 (s, 2H), 6.90 (s, 1H), 5.42 (s, 2H), 5.28 (d, J = 18.99 Hz, 1H), 5.24 – 5.14 (m, 2H), 4.53 – 4.45 (m, 2H), 4.31 – 4.24 (m, 2H), 3.99 (d, J = 11.79 Hz, 1H), 3.83 (d, J = 11.79 Hz, 1H), 3.46 (d, J = 11.13 Hz, 1H), 3.36 (t, J = 7.60 Hz, 1H), 3.18 – 3.10 (m, 2H), 2.42 – 2.34 (m, 6H), 2.33 – 2.24 (m, 4H), 1.90 – 1.82 (m, 2H), 1.76 (t, J = 7.86 Hz, 1H), 0.87 (t, J = 7.44 Hz, 3H). Example 4: Synthesis of mpGlyAsnAsnGly-Exatecan (S)-N1-((S)-4-amino-1-((2-(((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo- 2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)-4239-111442-022-oxoethyl)amino)-1,4-dioxobutan-2-yl)-2-(2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)propanamido)acetamido)succinimide Exatecan (10 mg, 1 Eq, 19 μmol) and (3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)propanoyl)glycyl-L-asparaginyl-L-asparaginylglycine (14 mg, 1.5 Eq, 28 μmol) were dissolved in DMF (0.38 mL), and treated with PYBOP (20 mg, 2.0 Eq, 38 μmol) and DIPEA (2.4 mg, 3.3 μL, 1.0 Eq, 19 μmol). The reaction was stirred for 4.5 hours at room temperature and was monitored by TLC and UPLC. Upon completion, the reaction was purified by Prep HPLC. LCMS rt = 2.32 min; m / z = 929.4 [M+H]; HPLC Purity = 98.2%; Overall yield = 20.0%.1H NMR (400 MHz, DMSO) δH / ppm 8.27 - 8.15 (m, 4H), 8.07 (d, J = 7.67 Hz, 1H), 7.77 (d, J = 10.93 Hz, 1H), 7.39 (bs, 1H), 7.31 (s, 1H), 7.30 (bs, 1H), 6.97 (s, 2H), 6.94 (bs, 1H), 6.71 (bs, 1H), 6.49 (bs, 1H), 5.58 – 5.51 (m, 1H), 5.41 (s, 2H), 5.27 (d, J = 18.97 Hz, 1H), 5.18 (d, J = 18.97 Hz, 1H), 4.49 - 4.42 (m, 1H), 4.40 – 4.33 (m, 1H), 3.73 (d, J = 6.07 Hz, 2H), 3.62 (dd, J = 2.06 Hz, 3.31 Hz, 2H), 3.57 (t, J = 7.62 Hz, 3H), 3.20 – 3.12 (m, 2H), 2.54 (t, J = 5.68 Hz, 2H), 2.44 – 2.33 (m, 6H), 2.24 – 2.04 (m, 2H), 1.86 (sept, J = 7.86 Hz, 2H), 0.87 (t, J = 7.36 Hz, 3H). Example 5: Synthesis of mpGlyAsnAsn(beta-Ala)-Exatecan (S)-N1-((S)-4-amino-1-((3-(((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo- 2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)- 3-oxopropyl)amino)-1,4-dioxobutan-2-yl)-2-(2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)propanamido)acetamido)succinimide Exatecan (10 mg, 1 Eq, 19 μmol) and mpGlyAsnAsn(beta-Ala)-OH (14 mg, 1.5 Eq, 28 μmol) were dissolved in DMF (0.38 mL), and treated with PYBOP (20 mg, 2.0 Eq, 38 μmol) and4239-111442-02DIPEA (2.4 mg, 3.3 μL, 1.0 Eq, 19 μmol). The reaction was stirred for 4.5 hours at room temperature and was monitored by TLC and UPLC. Upon completion, the reaction was purified by Prep HPLC. LCMS rt = 2.37 min; m / z = 943.8 [M+H]; HPLC Purity = 85.2%; Overall yield = 34.4%.1H NMR (400 MHz, DMSO) δH / ppm 8.49 (d, J = 8.48 Hz, 1H), 8.23 (t, J = 5.65 Hz, 1H), 8.18 (d, J = 7.68 Hz, 1H), 8.12 (d, J = 8.12 Hz, 1H), 7.80 (d, J = 10.87 Hz, 2H), 7.46 (bs, 1H), 7.32 (s, 1H), 7.25 (bs, 1H), 6.99 (s, 3H), 6.81 (bs, 1H), 6.51 (s, 1H), 5.60 – 5.53 (m, 1H), 5.43 (d, J = 2.75 Hz, 2H), 5.26 (d, J = 18.99 Hz, 1H), 5.18 (d, J = 18.99 Hz, 1H), 4.52 – 4.41 (m, 2H), 3.68 (d, J = 5.65 Hz, 2H), 3.59 (dd, J = 1.16 Hz, 7.54 Hz, 2H), 3.23 – 3.14 (m, 2H), 2.68 (quin, J = 1.90 Hz, 1H), 2.46 – 2.31 (m, 11H), 2.20 – 2.10 (m, 3H), 1.93 – 1.81 (m, 2H), 0.88 (t, J = 7.39 Hz, 3H). Example 6: Synthesis of mpGlyAsnAsnGABA-exatecan (S)-N1-((S)-4-amino-1-((4-(((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo- 2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)- 4-oxobutyl)amino)-1,4-dioxobutan-2-yl)-2-(2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)propanamido)acetamido)succinamide Exatecan (10 mg, 1 Eq, 19 μmol) and mpGlyAsnAsnGABA-OH (15 mg, 1.5 Eq, 28 μmol) were dissolved in DMF (0.38 mL), and treated with PYBOP (20 mg, 2.0 Eq, 38 μmol) and DIPEA (2.4 mg, 3.3 μL, 1.0 Eq, 19 μmol). The reaction was stirred for 4.5 hours at room temperature and was monitored by TLC and UPLC. Upon completion, the reaction was purified by Prep HPLC. LCMS rt = 2.41 min; m / z = 957.6 [M+H]; HPLC Purity = 95.2%; Overall yield = 33.9%.1H NMR (400 MHz, DMSO) δH / ppm 8.40 (d, J = 8.45 Hz, 1H), 8.23 (t, J = 5.81 Hz, 1H), 8.18 (d, J = 7.25 Hz, 1H), 8.09 (d, J = 8.04 Hz, 1H), 7.78 (d, J = 10.92 Hz, 1H), 7.71 (t, J = 5.44 Hz, 1H), 7.45 (bs, 1H), 7.30 (s, 1H), 7.23 (bs, 1H), 6.98 (s, 2H), 6.80 (bs,1H), 5.74 (s, 1H), 5.59 – 5.51 (m, 1H), 5.41 (bs, 2H), 5.23 (d, J = 18.86 Hz, 1H), 5.15 (d, J = 18.86 Hz, 1H), 4.50 – 4.38 (m, 2H), 3.66 (d, J = 5.44 Hz, 3H), 5.58 (t, J = 7.48 Hz, 3H), 3.16 (s, 3H), 3.08 – 2.99 (m, 2H), 2.56 (d, J = 6.83 Hz, 1H), 2.46 – 2.35 (m, 6H), 2.20 – 2.08 (m, 4H), 1.85 (sept, J = 7.77 Hz, 2H), 1.75 – 1.65 (m, 2H), 0.86 (t, J = 7.39 Hz, 3H).4239-111442-02Example 7: Preparation of 3A11-mpGlyAsnAsn(Beta-Ala)-Exatecan The 3A11 anti-FGFR4 antibody (7.5 mg, 640 µL of a 11.77 mg / mL stock solution) was added to 240 µL of DPBS containing 5 mM EDTA. TCEP (120 µL of 5mM stock, 12 eq.) was added and the antibody was incubated at 37°C for 2 hours. The linker payload, mpGlyAsnAsn(Beta-Ala)- Exatecan (25 eq., 250 µL of a 5 mM stock) and 1250 µL of DPBS containing 5 mM EDTA was added to the reduced antibody. After incubating at room temperature for 2 hours, the product was buffer- exchanged into DPBS using a 2.5 ml PD-10 desalting column. A second batch was conjugated via the same method and the two batches were mixed for final characterization. The final product was filter sterilized through a 0.2 mm filter. The DAR was measured via HPLC-MS, aggregation percentage was measure via SEC and hydrophobicity of ADCs was assessed via hydrophobic interaction chromatography (HIC). Approximately 9.4 mg of the final 3A11-mpGlyAsnAsn(Beta-Ala)-Exatecan was obtained from 15 mg of anti-FGFR4 antibody. The calculated DAR was 8.0 (FIG.3A) and no significant aggregation was observed (FIG.3B). The ADC was also homogeneous by hydrophobic interaction chromatography (HIC) (FIG.3C). Example 8: Preparation of anti-HEL-mpGlyAsnAsn(Beta-Ala)-Exatecan The anti-HEL antibody (7.5 mg, 540 µL of a 13.9 mg / mL stock solution) was added to 340 µL of DPBS containing 5 mM EDTA. TCEP (12 eq, 120 µL of 5 mM stock) was added and the antibody was incubated at 37°C for 2 hours. mpGlyAsnAsn(Beta-Ala)_Exatecan (25 eq., 250 µL of a 5 mM stock) and 1250 µL of DPBS containing 5 mM EDTA was added to the reduced antibody. After incubating at room temperature for 2 hours, the product was buffer-exchanged into DPBS using a 2.5 ml PD-10 desalting column. A second batch was conjugated via the same method and the two batches were mixed for final characterization. The final product was filter sterilized through a 0.2 mm filter. The DAR was measured via HPLC-MS, aggregation percentage was measured via SEC and hydrophobicity of ADCs was assessed via HIC. Approximately 10.6 mg of the final anti-HEL- mpGlyAsnAsn(Beta-Ala)-Exatecan was obtained from 15 mg of anti-HEL antibody. The calculated DAR was 8.0 (FIG.4A) and no significant aggregation was observed (FIG.4B). The ADC was also homogeneous by HIC (FIG.4C). Example 9: FGFR4 surface staining and quantification FGFR4 surface expression was tested in several FGFR4-expressing (RMS559, RD, RH30, JR, SCMC, RH4, MDA-MB-453, and Huh7) and non-expressing (RH30-FGFR4KO, RH4- FGFR4KO, and 7250) cell lines. Cells were detached from culture flasks using 0.05% trypsin and then washed twice with cold PBS and resuspended in 100 μL of cold FACS buffer (1X DPBS, 22% FBS, 2 mM EDTA, and 25 mM HEPES). Cells were incubated with 1 μg / ml of 3A11 scFvFc or isotype control, for 30 minutes at 4°C. After incubation, cells were washed twice with FACS buffer and resuspended in secondary goat anti-human IgG antibody (Jackson Laboratory) at 1:200 dilution in4239-111442-02FACS buffer. Following incubation, cells were washed three times with FACS buffer. Stained cells were analyzed on BD FACS Caliber or LSRFortessa. Data was analyzed and mean fluorescence intensity (MFI) was calculated for FGFR4 surface level measurement using Flow Jo software. FGFR4 surface molecules per cell were calculated post subtracting the background signal emanating from a respective isotype control antibody (Clone QA16A12 for human IgG1 antibody, Biolegend) by the QuantibriteTMPE Quantitation Kit (BD Biosciences, Cat# 340495) according to the manufacturer’s protocol. A representative flow cytometry plot showing differential levels of FGFR4 expression on RMS cell lines (RMS559, RD, RH30, JR, SCMC, RH4, RH30-FGFR4KO, RH4-FGFR4KO), breast cancer cell line MDA-MB-453, liver cancer cell line Huh7, and fibroblast 7250 cells is shown in FIG. 5 (left). Surface FGFR4 molecule numbers per cell of each cell line was estimated and quantified by PE quantitation beads (FIG.5, right). Example 10: 3A11 mAb is internalized by FGFR4-positive cells and trafficked to lysosomes The effectiveness of ADC-based therapy relies on internalization of receptor-ADC complexes by target cells, enabling intracellular release of payloads and inducing cytotoxicity (Li et al., Cancer Discov 10:674-687, 2020). To test the suitability of the 3A11 antibody in ADC development, the internalization of 3A11 was evaluated using a lysosomal pH imaging assay.3A11 was labeled with a pH-sensitive dye (FabFluor-pH), which only fluoresces at a low pH environment, allowing visualization of formation of endolysosomes. Significant internalization of 3A11 was observed in FGFR4-high-expressing RMS cell lines (RMS559 and JR, Table 2, FIG.6A) compared to the isotype IgG control (FIG.6A). In contrast, lower levels of 3A11 internalization were detected in FGFR4- medium-expressing cell lines (SCMC), and no internalization was observed in FGFR4 knockout cells (RH30-FGFR4KO or RH4-FGFR4 KO), confirming the FGFR4-dependent specificity of 3A11 internalization (FIGS.6A-6B). Interestingly, despite RH30 expressing high levels of FGFR4, the 3A11 internalization activity was much lower than RMS559 and JR, which may be attributed to the intrinsic properties of this cell line (FIGS.6B-6C). Furthermore, a significant correlation was observed between FGFR4 expression levels and 3A11 internalization activity in RMS cells (Fig.6C, p = 0.0002), indicating that specific binding of 3A11 to cell surface FGFR4 causes internalization of the antibody. Table 2. FGFR4 expression levels in tumor cell lines and potency of FGFR4-targeted ADCs α-FGFR4- α-FGFR4- FGFR4 4239-111442-02α-FGFR4- α-FGFR4- FGFR4 Cell / Tumor Type Sample Name MMAE Exatecan l l ll e- derived xenografts (CDXs), patient-derived xenografts (PDXs), breast cancer (BRCA), hepatocellular carcinoma (HCC) and hepatoblastoma (HBL). Data represent quantitative surface FGFR4 molecule numbers per cell in the indicated cell lines using a phycoerythrin (PE) fluorescence quantitation kit. This data provides insights into FGFR4 expression across different models. Columns 4-5. Percentage of area under the curve (AUC) calculated as (AUC of FGFR4-targeted ADC / AUC of isotype-control ADC) × 100%, indicating the relative potency of FGFR4-directed ADCs compared to isotype-control ADCs. Example 11: FGFR4-targeted ADCs FGFR4-targeted ADCs were developed using a microtubule inhibitor and a topoisomerase I (Topo I) inhibitor, which are standard-of-care agents for RMS including in the relapsed setting (Pacenta et al., J Clin Med 10:1416, 2021). For the microtubule inhibitor-based ADC, the FGFR4- specific monoclonal antibody 3A11 was conjugated to monomethyl auristatin E (MMAE) via the protease-cleavable valine-citrulline-p-aminobenzyl carbamate (VC-PABC) linker, generating α-4239-111442-02FGFR4-vc-MMAE (FIG.7A). For the Topo I inhibitor-based ADC, a legumain-cleavable mpGlyAsnAsn(βAla) linker, a target of lysosomal asparaginyl endopeptidase (Miller et al., Bioconjug Chem 32:842-858, 2021), was used to conjugate 3A11 to the potent Topo I inhibitor Exatecan, resulting in α-FGFR4-NNβA-exatecan (FIG.7A). The α-FGFR4-vc-MMAE ADC was designed with a drug-to-antibody ratio (DAR) of 4, while α-FGFR4-NNβA-exatecan had a DAR of 8 (FIG.7A). To generate isotype-matched ADC controls, an irrelevant monoclonal antibody targeting hen egg lysozyme (HEL) was conjugated to MMAE or Exatecan using the same linkers, ensuring comparable DARs. The two ADCs were compared across several human cancer cell lines, including RMSs with varying FGFR4 expression levels (Table 2). Both ADCs exhibited the greatest cytotoxic activity in FGFR4-high-expressing cell lines, RMS559 and JR (FIG.7B, Table 2). However, α-FGFR4-NNβA- exatecan demonstrated significantly higher cytotoxicity than α-FGFR4-vc-MMAE in RH30, JR, and SCMC cell lines, reflecting the superior potency of Exatecan as a payload against RMS (FIG.7B, Table 2). In contrast, the isotype control ADCs showed no cytotoxicity in any FGFR4-expressing RMS cell lines, confirming the target specificity of FGFR4-directed ADCs (FIG.7B, Table 2). All tested RMS cell lines were sensitive to free MMAE (IC50: 0.05 ~ 0.54 nM) and Exatecan (IC50: 0.19 ~ 0.99 nM) (FIG.13). Importantly, neither FGFR4-targeted ADC demonstrated growth-inhibitory effects in FGFR4 knockout cell lines (RH30 KO, RH4 KO) or human fibroblast 7250 cell line lacking FGFR4 expression (FIG.7B, Table 2). These data establish that the observed cytotoxic activity of FGFR4-targeted ADCs is dependent on FGFR4 expression. Furthermore, their potency strongly correlated with the expression levels of FGFR4 and 3A11 internalizing efficiency and was unrelated to their intrinsic drug sensitivity, as they all were sensitive to these drugs to varying degrees (FIGS. 7C-7D). Therefore, FGFR4-targeted ADCs are promising therapeutics for RMS treatment. Example 12: Mechanism of growth suppression of FGFR4-targeted ADCs To investigate the mechanism of growth suppression triggered by the FGFR4-targeted ADC, PARP cleavage, a hallmark of apoptosis mediated by caspase-3 / 7, was examined. RMS559, RH4, and RH4-FGFR4 KO cell lines were treated with α-FGFR4-vc-MMAE, α-HEL-vc-MMAE, MMAE alone, or unconjugated 3A11 antibody. Western blot analysis revealed increased PARP cleavage in RMS559 and RH4 cells treated with α-FGFR4-vc-MMAE, while control ADC (α-HEL-vc-MMAE) and unconjugated 3A11 mAb did not result in PARP cleavage. Furthermore, α-FGFR4-vc-MMAE did not induce PARP cleavage in RH4-FGFR4 KO cells, confirming FGFR4 dependency (FIG.8A). To validate this finding, caspase-3 / 7 activity was quantified using a Caspase-Glo assay. Significantly increased activity was observed in RMS559 and RH4 cells treated with α-FGFR4-vc-MMAE compared to α-HEL-vc-MMAE, whereas no caspase activity was observed in RH4-FGFR4 KO cells (FIG.8B).4239-111442-02Cell apoptosis resulting from DNA damage caused by α-FGFR4-NNβA-exatecan was evaluated to detect phosphorylated Chk1 (pChk1) and histone H2A.X (γH2A.X), markers of DNA damage (Furuta et al., J Biol Chem 278:20303-20312, 2023; Xiao et al., J Biol Chem 278:21767- 21773, 2003), and cleaved PARP and active Caspase 3, markers of apoptosis. Treatment of RMS559, and RH4 with α-FGFR4-NNβA-exatecan (13.33 nM) for 24-72 hours led to increased pChk1, and cleaved PARP comparable to the effects observed with Exatecan alone, measured by Western blotting analysis (FIG.8C). In contrast, α-FGFR4-NNβA-exatecan ADC did not induce these markers in RH4- FGFR4 KO cells (FIG.8C). No increase of these markers was observed in control cells including treatment of 3A11 antibody alone, α-HEL-NNβA-exatecan, or untreated controls (FIG.8C). These results were validated using flow cytometry (FIG.8D), indicating Exatecan released from α-FGFR4- NNβA-exatecan ADCs exerts potent Topo I inhibition, leading to DNA damage and apoptosis in FGFR4-expressing cells. Bystander effects of ADC amplify the cytotoxic effects on other cancer cells when payload is released from a targeted cancer cell (Staudacher and Brown, Br J Cancer 117:1736-1742, 2017). To assess bystander killing effects of both ADCs, equal numbers of GFP-labeled RH4 cells and mCherry- expressing RH4-FGFR4 KO cells were co-cultured for 5 days (FIGS.8E and 8F), and flow cytometry was used to measure the composition of GFP+and mCherry+ cells (FIG.8E). At 11 nM (1.67 μg / mL), α-FGFR4-vc-MMAE exhibited clear bystander killing, effectively eliminating all FGFR4 KO cells, whereas α-FGFR4-NNβA-exatecan at 22 nM (3.33 μg / mL) showed no significant cytotoxicity toward FGFR4 KO cells (FIG.8F). Control ADCs had no detectable effect, further validating the bystander activity of α-FGFR4-vc-MMAE. These findings align with previous reports of MMAE-based ADCs exhibiting a strong bystander effect, where the cytotoxic payload can diffuse from antigen-positive cells to neighboring antigen-negative cells, enhancing overall antitumor efficacy (Staudacher and Brown, Br J Cancer 117:1736-1742, 2017). In contrast, Exatecan-based ADCs displayed a more limited bystander effect due to its limited membrane-permeability compared to MMAE (Khera et al., Mol Cancer Ther 21:310-321, 2022). Example 13: Pharmacokinetics profiling of FGFR4-targeted ADCs To evaluate the stability and systemic behavior of FGFR4-targeted antibody-drug conjugates (ADCs), their pharmacokinetic (PK) properties in NSG mice were characterized by measuring serum levels of total IgG, conjugated drug, and free drug following a single intravenous (IV) dose (FIGS. 9A-9C and Table 3). Free MMAE was detected at low concentrations, with a maximum serum level of 4.2 ± 1.51 ng / mL at 24 hours post-injection (FIG.9A), consistent with previously reported values for MMAE-based ADCs (Chang et al., Pharmaceutics 15(4):1132, 2023). In contrast, free β-ala- exatecan levels were below the lower limit of quantification (1 ng / mL, not detected), indicating minimal systemic release of the exatecan payload.4239-111442-02Pharmacokinetic analysis revealed that the exatecan-based ADC exhibited a longer half-life (T1 / 2), and lower clearance (CL) compared to the MMAE-based ADC, suggesting prolonged systemic retention (FIG.9D). Conversely, the MMAE-based ADC demonstrated a higher volume of distribution (Vd) and steady-state volume of distribution (Vss), indicative of broader extravascular tissue distribution and more rapid clearance (FIG.9D). Notably, systemic exposure, as measured by area under the concentration–time curve (AUC), was significantly greater for the exatecan-conjugated ADC, reflecting more sustained drug availability in circulation (FIG.9D). These PK characteristics, longer T₁ / ₂, higher AUC, and lower CL, suggest that exatecan-based ADCs may offer improved clinical efficacy. Additionally, the lower Vd and Vss values may translate to reduced off-target tissue exposure and potentially lower toxicity. Interestingly, the enhanced PK exposure of the exatecan ADC was observed despite its higher drug-to-antibody ratio (DAR), which is typically associated with increased clearance (Sun et al., Bioconjug Chem 28(5):1371-1381, 2017). This unexpected finding suggests that the polarity introduced by the AsnAsn motif in the linker may contribute favorably to the systemic behavior of the exatecan ADC. Finally, the close concordance between AUC values for total IgG and conjugated drug strongly supports the stability of the linker in vivo, indicating minimal payload release during circulation (FIG.9D). Table 3. Total IgG on FGFR4-targeted ADCs in serum detected by MSD assay Total IgG (ng / ml) on ADC 8 6 6 3 5 4 6 3 MMAE or Exatecan on FGFR4-targeted ADCs in serum detected by MSD assay MMAE (ng / ml) on ADC Exatecan (ng / ml) on ADC 4239-111442-02MMAE (ng / ml) on ADC Exatecan (ng / ml) on ADC Time α-FGFR4-MMAE α-FGFR4-Exatecan 1 2 6 6 5 7 6 4 rior efficacy in FN-RMS cell line models To determine the therapeutic potential of FGFR4-targeted ADCs, their efficacy was evaluated in a cell line-derived xenograft (CDX) RMS559, a highly aggressive FN-RMS with an FGFR4 V550L activation mutation (McKinnon et al., Oncogene 37:2630-2644, 2018) and high FGFR4 expression (7,175 molecules / cell in CDX) (Tian et al., Cell Rep Med 4:101212, 2023; Tian et al., Nat Commun 15:6222, 2024). A dose-finding study was first conducted to determine both efficacy and tolerability of α-FGFR4-vc-MMAE (0.3, 1, or 3 mg / kg, administered twice weekly for two weeks; FIG.14A) and α-FGFR4-NNβA-exatecan (a single dose of 3 or 10 mg / kg; FIG.15A). α-FGFR4-vc-MMAE exhibited dose-dependent tumor growth inhibition and improved survival, with the highest dose (3 mg / kg) inducing significant tumor regression following a single treatment cycle (FIGS.14B-14E). No significant weight loss or toxicity was observed, indicating good tolerability (FIGS.14F-14H). The control ADC, α-HEL-vc-MMAE, did not inhibit tumor growth, confirming that cytotoxicity of α-FGFR4-vc-MMAE depends on FGFR4 binding (FIGS. 14B-14H). In a confirmatory study using the same model (n = 10, FIG.10A), a single cycle of 3 mg / kg α-FGFR4-vc-MMAE (twice weekly for two weeks) delayed tumor growth in 6 mice and completely eradicated tumors in 4 mice (FIG.10B), resulting in a 70% survival rate (FIG.10D). For α-FGFR4-NNβA-exatecan ADC, a single 3 mg / kg dose failed to suppress tumor growth or improve survival (FIGS.15B-15D). Increasing the dose to 10 mg / kg led to a temporary rapid tumor shrinkage followed with a tumor regrowth in two weeks, likely due to the aggressive nature of RMS559 (FIGS.15B-15D). Due to the low toxicity observed for this ADC, a decision was made to administer two doses of 10 mg / kg α-FGFR4-NNβA-exatecan (FIG.10A). Remarkably, this treatment resulted in a complete tumor eradication and a 100% survival rate without obvious toxicity such as weight loss and behavioral abnormalities (FIGS.10C and 10E). These data demonstrate that although4239-111442-02both ADCs displayed a comparable in vitro efficacy against RMS559 cells, Exatecan-based ADCs exhibited a superior therapeutic efficacy in RMS559 CDX models compared to MMAE-based ADCs. Next, the mechanisms of ADC-mediated tumor control in vivo were examined. Both ADCs significantly increased cleaved caspase-3 staining compared to isotype control ADCs or vehicle controls, indicating ADCs induced apoptosis (FIGS.10F-10I). However, neither treatment significantly reduced tumor cell proliferation, as shown by unchanged Ki67+cell percentages (FIGS. 10F-10I). Notably, only α-FGFR4-NNβA-exatecan treatment led to a significant reduction in FGFR4+tumor cells, as measured by the FGFR4 H-score (FIGS.10G and 10I). Therefore, consistent with the mechanisms of action of the payloads, both FGFR4-targeted ADCs induce tumor regression primarily through apoptosis rather than proliferation arrest, with Exatecan-based ADCs offering a superior efficacy. Example 15: FGFR4-targeted ADCs are efficacious in FP-RMS CDX and PDX models Antitumor activity of both ADCs was further evaluated in fusion-positive RH4 xenografts, which have moderate FGFR4 expression (3,637 molecules per cell, FIG.11A). A single cycle of α- FGFR4-vc-MMAE (3 mg / kg, twice weekly for two weeks) delayed tumor growth (FIG.11B), improving survival by 30% (FIG.11D). In contrast, a single 10 mg / kg dose of α-FGFR4-NNβA- exatecan provided much better tumor control (FIG.11C) achieving 100% survival (FIG.11E). These results further support that Exatecan-based ADCs exhibit superior potency compared to MMAE-based ADCs, even in tumors with a moderate FGFR4 expression. Next, the therapeutic efficacy of these ADCs was evaluated in an FP-RMS patient-derived xenograft (PDX) model, SJRHB013759 (1,337 molecules per cell, FIG.11F). A single treatment cycle of α-FGFR4-vc-MMAE (3 mg / kg, twice weekly for two weeks) resulted in a complete tumor regression in 4 out of 5 mice, with one mouse experiencing tumor relapse approximately 60 days after the first treatment started (FIG.11G), achieving an 80% survival rate (FIG.11I). All mice in control groups succumbed to the tumors within 60 days after initiation of the treatments. The Exatecan-based ADC (α-FGFR4-NNβA-exatecan, 10 mg / kg) demonstrated even greater potency, inducing complete tumor regression (FIGS.16A-16D). Interestingly, the isotype control ADC led to partial tumor regression with regrowth observed by day 45. Given the potential of Exatecan leakage from the isotype IgG control ADC, a lower-dose regimen (3 mg / kg for two doses) was tested. This approach effectively controlled tumor growth for 45 days, though relapse occurred in 4 out of 8 mice (FIG. 11H). Notably, a second cycle of 3 mg / kg successfully regressed large tumors (1,500 ~ 2,000 mm³) (FIG.11H), ultimately achieving complete tumor control and a 100% survival rate (FIG.11J). These data demonstrate that both FGFR4-ADCs exhibit robust antitumor activity in FP-RMS, with a durable tumor control by the Exatecan-based ADCs.4239-111442-02Example 16: Efficacy of FGFR4-targeted ADCs in other FGFR4-expressing cancer models FGFR4 mRNA expression in various pediatric and adult tumors, including hepatoblastoma (HBL), liver hepatocellular carcinoma (LIHC), cholangiocarcinoma (CHOL), and certain breast invasive carcinoma (BRCA) was previously reported (Tian et al., Cell Rep Med 4:101212, 2023). High FGFR4 expression [log2(TPM+1) ≥ 6.5, TPM = 90] can be detected in approximately 75.19% of RMS, 80% of HBL, 27.5% of desmoplastic small round cell tumor (DSRCT), and 100% of yolk sac tumors (YST) (FIG.12A). In adult tumors, 62.79% of CHOL, 42.64% of LIHC, 34.18% of adrenocortical carcinoma (ACC), 30.3% of rectal adenocarcinoma (READ), 28.66% of colon adenocarcinoma (COAD), 25% of kidney renal papillary cell carcinoma (KIRP), 14.53% of stomach adenocarcinoma (STAD), and 3.04% of BRCA exhibited high FGFR4 expression (FIG.12A). To examine FGFR4 protein expression, immunohistochemistry (IHC) was performed on tissue microarrays (TMAs) comprising of breast cancer (n = 76) and hepatocellular carcinoma (HCC) (n = 16) samples. Three percent of breast cancers were found to have moderate FGFR4 staining, while 13% with minimal signal. In HCC samples, 13% had moderate signals and the same percentage had minimal signal (FIG.12B). Flow cytometry analysis of breast cancer (MDA-MB-453, CAMA-1, BT- 474, SKBR3, MDA-MB-134 IV) and liver cancer (Huh7, Hep3B, HepG2) cell lines reveals high FGFR4 expression in MDA-MB-453 (26,202 molecules / cell), CAMA-1 (10,226 molecules / cell), Hep3B (10,082 molecules / cell), Huh7 (7,247 molecules / cell), and HepG2 (7,214 molecules / cell), and moderate expression in BT-474 (3,396 molecules / cell) (FIG.12C). These data validate high FGFR4 expression in these breast and liver cancer models, suggesting for the potential of FGFR4-targeted therapy against these malignancies. Next, the efficacy of FGFR4-targeted ADCs was evaluated in FGFR4-expressing breast and liver cancer models. The MMAE-based ADC (α-FGFR4-vc-MMAE) effectively inhibited growth in MDA-MB-453, CAMA-1, and BT-474 (FIG.12D, Table 2). While exhibiting minimal activity against BT-474, α-FGFR4-NNβA-exatecan ADC showed comparable potency to α-FGFR4-vc- MMAE for MDA-MB-453 cells but was significantly more effective against Huh7 cells (FIG.12D, Table 2). Both ADCs demonstrated limited efficacy in Hep3B and HepG2 (FIG.17A). All these cell lines mostly displayed slightly lower sensitivity to free MMAE (IC₅₀: 0.17 ~ 0.37 nM) than RMS cell lines (IC₅₀: 0.05 ~ 0.54 nM). In contrast, MDA-MB-453 and Huh7 showed higher sensitivity to free Exatecan than CAMA-1, BT-474, Hep3B, and HepG2 (FIGS.17B and 17C). These results suggest that intrinsic resistance of these cells to the cytotoxic payloads may contribute to the limited efficacy of FGFR4-targeted ADCs in certain tumor models, despite high FGFR4 expression. To further evaluate their therapeutic efficacy, both ADCs were tested in an ER-negative, PR- negative, HER2-positive breast cancer xenograft mouse model (MDA-MB-453, FIG.12E). A single treatment cycle of α-FGFR4-vc-MMAE (3 mg / kg) or α-FGFR4-NNβA-exatecan (10 mg / kg) resulted in complete tumor regression lasting 59 and 80 days, respectively (FIG.12F). Tumor relapse was observed by day 98, with α-FGFR4-vc-MMAE-treated tumors regrowing to 200 ~ 650 mm³ and α-4239-111442-02FGFR4-NNβA-exatecan-treated tumors to 100 ~160 mm³. To address relapse, a second treatment cycle was administered. Retreatment with α-FGFR4-vc-MMAE (3 mg / kg, four doses over two weeks) initially suppressed tumor regrowth but failed to achieve long-term control, with tumors recurring after day 116. In contrast, a second 10 mg / kg dose of α-FGFR4-NNβA-exatecan completely eliminated relapsed tumors, achieving 100% survival (FIG.12G). These results suggest that while both FGFR4-targeted ADCs effectively controlled tumor growth, relapses occurred earlier with α- FGFR4-vc-MMAE, and retreatment provided only temporary suppression. Conversely, α-FGFR4- NNβA-exatecan demonstrated superior therapeutic durability, with a second dose successfully eradicating relapsed tumors, highlighting Exatecan-based ADCs as a more durable therapeutic option for this FGFR4-expressing breast cancer model. Example 17: Materials and Methods This example provides the materials and experimental procedures used for the studies described in Examples 10-16. Cell lines, cell culture, CDX and PDX tumors Human RMS cell line RMS559 was obtained from Dr. Jonathan Fletcher at Brigham and Women’s Hospital, Boston, USA. RH30 and RH4 were provided by Dr. Peter Houghton, Greehey Children’s Cancer Research Institute, San Antonio, Texas, USA. JR was a gift from Dr. Corinne M. Linardic at Duke University School of Medicine, Durham, NC, USA. Dr. Lee Helman from Children's Hospital Los Angeles, CA, USA, provided RD. Dr. Janet Shipley, Institute of Cancer Research, London, England provided SCMC. Dr Andras Heczey provided the luciferase-expressing Huh7 cell line (Baylor College of Medicine, Houston, TX). CAMA-1 was provided by Dr. Esta Sterneck, National Cancer Institute, Frederick, MD, USA. Human liver cancer cell lines Hep3B and HepG2, human breast cancer cell lines MDA-MB-453, BT-474, SKBR3, and MAD-MB-134 IV were purchased from the American Type Culture Collection (ATCC, Manassas, VA). RMS cell lines RMS559, RH30, SCMC, RH4, and RD, and HCC cell lines Huh7, Hep3B, and Huh7 cells were cultured in Dulbecco Modified Eagle Medium (DMEM, Quality Biological), supplemented with 10% FBS (Gibco, Life Technologies), 10 mM HEPES, 100 U / mL penicillin, 100 μg / ml streptomycin and 2 mM L-glutamine (Gibco, Life technologies). JR, MDA-MB-453, SKBR3, CAMA-1, BT-474, and MAD-MB-134 IV cells were cultured in RPMI1640, supplemented with 10% FBS (Gibco, Life Technologies), 100 U / mL penicillin, 100 μg / ml streptomycin, and 2 mM L- glutamine. All cell lines were STR fingerprinted to confirm their identity every 6 months and regularly tested to be mycoplasma negative by a MycoAlert kit (Lonza). FGFR4-KO (FGFR4-guide: 5’-GATCGTGGAGTGCGCCGCCAA-3’ SEQ ID NO: 20) RH30 or RH4 were generated by CRISPR / Cas9 gene-editing technology as previously described (Tian et al., Nat Commun 15:6222, 2024).4239-111442-02Patient-derived xenograft (PDX) SJRHB013759_X1 (FP-RMS) and SJRHB015720_X1 (MYOD1 mutant RMS) were obtained from St. Jude Children’s Research Hospital (Memphis, Tennessee, USA) and expanded in NSG mice. Antibody production The anti-FGFR4 antibody was engineered by fusing the sequence encoding the Fab region of monoclonal antibody (mAb) 3A11 to the human immunoglobulin G1 (IgG1) Fc domain. The chimeric human 3A11 antibody was expressed in a CHO (Chinese Hamster Ovary) cell system and purified by Biointron Biological Inc. A human IgG1-Kappa isotype control, V6 α-Hen Egg Lysozyme (HEL), was purchased from Shanghai Abinvivo (Cat # B117901; Biointron Biological Inc., Metuchen, NJ). Antibody purity was assessed by SDS-PAGE and size-exclusion high-performance liquid chromatography (SEC-HPLC). Only antibodies with less than 5% aggregate content were used for antibody-drug conjugate (ADC) production. ADC production and purification The chimeric human 3A11 antibody, prepared in 5 mM EDTA / PBS, was reduced using either 3 or 12 molar equivalents of Tris (2-carboxyethyl) phosphine (TCEP) at 37°C for 1.5 hours to cleave interchain disulfide bonds. Following reduction, 8 or 25 molar equivalents of the drug-linker ValCitPABC-MMAE or mpGlyAsnAsn(β-Ala)-Exatecan were separately added to the antibody. The mixtures were incubated at room temperature for 3 hours to complete conjugation. The reaction products were buffer-exchanged into DPBS using 2.5 mL PD-10 desalting columns packed with Sephadex G-25 resin (Cytiva) and concentrated as required using 30 kDa molecular weight cutoff spin columns. The final ADC products were sterile filtered through 0.2 µm filters. The drug-antibody ratio (DAR) was determined using HPLC-MS, yielding a DAR of approximately 4.0 for α-FGFR4-vc- MMAE and 8.0 for α-FGFR4-NNβA-exatecan. Size-exclusion chromatography (SEC) analysis confirmed minimal aggregation. Isotype control IgG-ADCs were synthesized following the same protocol as α-FGFR4-vc- MMAE and α-FGFR4-NNβA-exatecan, achieving comparable DAR values. Quantitation of FGFR4 molecules on cell lines FGFR4 expression levels on tumor cells were quantified as previously described (Tian et al., Nat Commun 15:6222, 2024). Briefly, single-cell suspensions of tumor cell lines were stained with 1 µg / ml of anti-human FGFR4 antibody (clone 3A11) for 30 minutes at 4°C. After two washes, cells were incubated with R-Phycoerythrin (R-PE) AffiniPure F(ab’)2 Fragment Goat Anti-Human IgG, Fcγ Fragment-specific antibody (1:200 dilution, Cat# 109-116-170, Jackson ImmunoResearch Laboratories) in FACS buffer. Following additional washes, FGFR4 signal was quantified by flow cytometry. To determine the number of FGFR4 molecules per cell, fluorescence intensity was4239-111442-02calibrated using the Quantibrite PE Quantitation Kit (BD Biosciences, Cat# 340495) according to the manufacturer’s instructions. Background signal was corrected by subtracting the fluorescence intensity of the corresponding isotype control antibody (Clone QA16A12 for human IgG1, BioLegend) to ensure accurate quantification. Anti-FGFR4 antibody internalization assays Cells were seeded into clear 96-well plates at an appropriate density and incubated overnight at 37°C in a humidified atmosphere with 5% CO₂. The chimeric anti-FGFR4 antibody (3A11) and human IgG1 isotype control antibodies were labeled using the INCUCYTE FabFluor-pH Antibody Labeling Reagent (Cat# 4722, Sartorius) following the manufacturer’s instructions. The labeled antibodies were then diluted to the desired concentrations and added to the cells. Internalization was quantified every 30 minutes over 24 hours in an INCUCYTE S3 live-cell imaging system. Fluorescence from internalized antibodies and cell confluence was quantified using INCUCYTE Software (2024 version). Fluorescence signal normalized by cell confluence was analyzed and visualized in the GraphPad Prism (version 10.1.1). Cell Viability Assay Tumor cells were seeded into white 96-well plates and incubated overnight at 37°C in a humidified incubator with 5% CO₂. A serial dilution of the test compounds, including α-FGFR4-vc- MMAE ADC, α-HEL-vc-MMAE control ADC, free MMAE, α-FGFR4-NNβA-exatecan ADC, α- HEL-NNβA-exatecan control ADC, and free Exatecan, were added to cells. Cell viability was assessed after 120 hours incubation using the CellTiter-Glo 2.0 Cell Viability Assay (Cat# G9242, Promega) following the manufacturer’s protocol. Luminescence was measured using a Spark Multimode Microplate Reader (Tecan), and the signals were normalized to the respective vehicle controls (PBS or DMSO). Data analysis, including IC50 and Area Under the Curve (AUC) calculations, was performed using GraphPad Prism (version 10.1.1). The potency of ADCs was determined by calculating the percentage of AUC for the FGFR4-targeted ADCs relative to the AUC of the isotype control ADCs. Western Blots for testing action mechanism of FGFR4-targeted ADCs RMS559, RH4, and RH4 FGFR4 KO cells were individually treated with 1 μg / mL 3A11 mAb, α-HEL-vc-MMAE, α-FGFR4-vc-MMAE, and MMAE for 24 hours; or 1 μg / mL 3A11 mAb, α- HEL-NNβA-exatecan, α-FGFR4-NNβA-exatecan, and Exatecan for 24, 48, or 72 hours. Cells were then harvested and lysed using RIPA buffer (Cat# 9806, Cell Signaling Technology) supplemented with Halt Protease & Phosphatase Inhibitor Cocktail (Cat# 78442, Thermo Fisher Scientific). Protein concentrations were measured with the Pierce Bradford Protein Assay Kit (Cat# 23200, Thermo Scientific) according to the manufacturer’s instructions. Equal amounts of protein samples were4239-111442-02loaded onto Bis-Tris gels, separated by SDS-PAGE, and transferred onto PVDF membranes. Membranes were blocked in an appropriate blocking buffer and incubated overnight at 4°C with primary antibodies specific to the targets of interest. After washing, membranes were incubated with HRP-conjugated secondary antibodies for 1 hour at room temperature. The chemiluminescent signal was developed and visualized using the ChemiDoc Imaging System (Bio-Rad). The primary antibodies used to assess apoptosis or DNA damage are as follows: anti-PARP (Cat#9542, Cell Signaling), anti-phospho-Chk1 (Cat# 133D3, Ser345) rabbit mAb, and anti-phospho- Histone H2A.X (Ser139) antibody (clone 20E3, Cat# 9718S, Cell Signaling Technology). Primary antibodies for loading controls included anti-β-actin (8H10D10) mouse mAb (Cell Signaling Technology, Inc.), anti-Chk1 (2G1D5) mouse mAb, and anti-Histone H2A.X antibody (Cat# 2595S, Cell signaling). Flow cytometry analysis of γ-H2A.X and active caspase-3 expression on tumor cells RMS559, RH4, and RH4 FGFR4 KO cells were treated with 3 μg / mL 3A11 mAb, α-HEL- NNβA-exatecan, α-FGFR4-NNβA-exatecan, and Exatecan for 48 hours at 37°C in a humidified atmosphere with 5% CO₂. After treatment, cells were harvested and prepared as single-cell suspensions. Cells were fixed using BD CYTOFIX Fixation Buffer (Cat# 554655, BD Biosciences) and permeabilized with BD Perm / Wash Buffer (Cat# 554723, BD Biosciences) according to the manufacturer’s protocol. Cells were subsequently stained in BD Perm / Wash Buffer with ALEXA FLUOR 647 Mouse anti-H2AX (pS139) (Cat# 560447, BD Pharmingen) and PE Rabbit Anti-Active Caspase-3 antibody (Cat# 570184, BD Pharmingen). Samples were analyzed using either the LSR Fortessa or FACSymphony A5 Cell Analyzer System (BD Biosciences). Data acquisition and analysis were conducted with FlowJo™ software to quantify γ-H2A.X and active caspase-3 expression. FGFR4-Immunohistochemistry (IHC) on TMAs Breast cancer tissue microarrays (TMA, BR1506) and liver cancer TMA (LV487b) were obtained from Tissuearray.Com (Derwood, MD). FGFR4 IHC was performed using a Leica BOND Rx autostainer (Leica Biosystems) with the Bond Polymer Refine Detection Kit (DS 9800, Leica Biosystems). Briefly, formalin-fixed, paraffin-embedded (FFPE) TMA sections underwent antigen retrieval in Tris-EDTA buffer (pH 9.0) at 95°C for 20 minutes. Sections were then incubated with a rabbit monoclonal anti-FGFR4 antibody (Clone D3B12; Cell Signaling Technology, Denver, CA) at a 1:50 dilution for 1 hour at room temperature. Detection of bound primary antibodies was achieved using Alkaline Phosphatase AFFINIPURE Goat Anti-Rabbit IgG (H+L) secondary antibody (Cat# 111-055-003, Jackson ImmunoResearch) diluted at 1:500. Slides were scanned at 20× magnification using the PhenoImager whole-slide scanner (Akoya Biosciences).4239-111442-02IHC staining results were reviewed and scored by a board-certified pathologist. Staining intensity thresholds were established to classify cells as negative, 1+, 2+, or 3+. H-scores were calculated using the formula: H-score = [1*(%1+) + 2*(%2+) + 3*(%3+)]. Caspase 3, Ki67, and FGFR4 immunohistochemistry (IHC) For IHC study of α-FGFR4-vc-MMAE, NSG mice bearing RMS559 or RH4 tumors (~250 mm³) received two doses of 3 mg / kg α-FGFR4-vc-MMAE or α-HEL-vc-MMAE and vehicle control over one week. Tumors were harvested 24 hours after the final treatment. For the study of α-FGFR4- NNβA-exatecan, NSG mice bearing RMS559 tumors (~250 mm³) received a single dose of 10 mg / kg α-FGFR4-NNβA-exatecan or α-HEL-NNβA-exatecan. Tumors were harvested 72 hours post- treatment. All harvested tumors were fixed in 10% neutral-buffered formalin and processed into paraffin-embedded (FFPE) blocks. IHC was performed using the following primary antibodies: anti- human Ki67 (Cat# 12202,1:200 dilution, Cell Signaling Technology), anti-human cleaved caspase-3 (Cat# 9661, 1:800 dilution, Cell Signaling Technology), or anti-human FGFR4 antibody (Cat# CST8562, 1:100 dilution, Cell Signaling Technology). Whole Slide Imaging (WSI) was conducted using an Aperio ScanScope XT (Leica) at 200× magnification in a single z-plane. Tumor tissue was annotated to exclude areas of necrosis and section artifacts during quantification. Thresholds for positivity were determined using positive and negative controls. FGFR4 staining is reported as an H-Score, Ki67 as the % of positive cells, and cleaved caspase 3 as the % positive pixels. Bystander killing assay Bystander killing effect of FGFR4-targeted ADCs (α-FGFR4-vc-MMAE and α-FGFR4- NNβA-exatecan) and isotype control IgG-ADCs (α-HEL-vc-MMAE and α-HEL-NNβA-exatecan) was evaluated using an in vitro co-culture system. GFP-expressing FGFR4-positive RH4 cells were co-cultured with mCherry-labeled RH4-FGFR4 KO cells in 6-well plates. After a five-day incubation with the respective ADC treatments, adherent cells were harvested, and cells were quantified using flow cytometry (BD Fortessa SOPRI). The total cell number and the ratio of GFP⁺ RH4 and mCherry⁺ RH4-FGFR4 KO cells were determined using COUNTBRIGHT Absolute Counting Beads (Cat# C36950, Thermo Fisher) and analyzed with FlowJo software. Pharmacokinetic studies Pharmacokinetic analysis was performed using 5~8-week-old NSG mice, which were randomly assigned to two groups. Baseline serum samples were collected before injection. Mice received a single intravenous dose of either 3 mg / kg α-FGFR4-vc-MMAE or 10 mg / kg α-FGFR4- NNβA-exatecan, and then blood was collected at 15 minutes, 6 hours, 24 hours, 48 hours (2 days), 964239-111442-02hours (4 days), 216 hours (9 days), 336 hours (14 days), and 21 days post-injection. At each time point, serum was separated by centrifugation at 2000 rpm for 10 minutes and stored at -80°C until analysis. Electrochemiluminescence (ECL) Meso Scale Discovery (MSD) assays were used for quantification of α-FGFR4-vc-MMAE and α-FGFR4-NNβA-exatecan in serum samples. Briefly, streptavidin assay plates were blocked with blocking buffer for 1 hour at room temperature with constant shaking. The biotinylated recombinant human FGFR4 / CD334 protein (Cat# RP02357, Abclonal) solution (25 μL) was added to the assay microplates. After incubation for 1 hour, plates were washed and the serial diluted ADC calibrators (for standard curve construction), diluted mice serum samples, or reference samples (25 μL) were added to further incubate for 1 hour. After a wash step, the Sulfo-Tagged detection antibody solution (25 μL) (SULFO-TAG anti-human IgG antibody (Cat# D21ADF-3, MSD), SULFO-TAG monoclonal anti-DXD&Exatecan antibody (Cat# DXD- M684, Acro Biosystems), or SULFO-TAG monoclonal anti-MMAE&MMAF antibody (Cat# MME- M5252, Acro Biosystems)) was added and incubated for 1 hour. After washing, a 2X Read Buffer was added, which was read with a QuickPlex instrument (MSD) within 20 minutes. The data were analyzed with WorkBench 4.0 software (Meso-Scale Diagnostics), and concentration of the analytes was determined by use of the 5 Parameter Logistic nonlinear regression model. The concentration- time data were analyzed by non-compartment pharmacokinetic analysis using Phoenix WinNonlin Version 8.4 (Certara, NJ, USA). Xenograft mouse models Animal studies (Protocol #GB-012) were conducted in accordance with the Institutional Animal Care and Use Committee (IACUC) guidelines at the NIH. The protocol was approved by the IACUC, and all procedures adhered to institutional standards. Female NSG mice (NOD.Cg- PrkdcscidIl2rgtm-1Wjl / SzJ; aged 5–8 weeks) were in-house bred (NCI CCR Animal Resource Program, NCI Biological Testing Branch) and housed under IVM Microisolator conditions with a 12- hour light / dark cycle (lights on from 6 am to 6 pm). For subcutaneous CDX or PDX models, RMS CDX cells (2E6 of RMS559, 5E6 of RH4), RMS PDX cells (5E6 of FP-RMS SJRHB013759_X1, or 5E6 of MYOD-mutant-RMS SJRHB015720_X1), or breast cancer cells (5E6 of MDA-MB-453) were resuspended in Matrigel (Corning) after washing and subcutaneously injected into each NSG mice. Treatment was started when average tumor volumes reached to ~100 mm3, with doses and frequencies of treatments indicated in each figure. α-HEL-vc-MMAE, α-HEL-NNβA-exatecan or HBSS were used as isotype or vehicle controls. Tumor growth was measured twice weekly using calipers, and tumor volume wascalculated using the formula: ^^^^^^ = (^^^^^ℎ × width^) / 2. Mice were euthanized if tumorsreached or exceeded 2 cm in any dimension or if mice exhibited signs of distress or toxicity, including >20% body weight loss.4239-111442-02Statistics GraphPad Prism 8 was used for graphing and data analysis. Log-rank statistical tests were used for survival analyses. An unpaired, two-tailed Student’s t-test was used to calculate the significant difference between 2 groups. An ordinary one-way ANOVA was used for multiple group comparisons. A two-way ANOVA was used for in vivo tumor growth curves. p-values of less than 0.05 were considered statistically significant. Statistical analysis method is also described in the individual figure legends. Example 18: Analysis of chimeric and humanized 3A11 binding to FGFR4 proteins The chimeric 3A11 (c3A11) antibody includes the VH and VL domains of mouse antibody 3A11 (set forth as SEQ ID NO: 1 and SEQ ID NO: 2, respectively) and the heavy chain and light chain constant regions of human IgG1 (set forth as SEQ ID NO: 17 and SEQ ID NO: 18, respectively). Three humanized versions of the 3A11 antibody were generated, which are referred to as h3A11-1 (VH = SEQ ID NO: 9; VL = SEQ ID NO: 10), h3A11-2 (VH = SEQ ID NO: 11; VL = SEQ ID NO: 12) and h3A11-3 (VH = SEQ ID NO: 13; VL = SEQ ID NO: 14). The humanized 3A11 antibodies also included the human IgG1 constant heavy chain and light chain constant regions (SEQ ID NO: 17 and SEQ ID NO: 18, respectively). The binding properties of c3A11 and h3A11-2 were tested by ELISA and BLI. For the ELISA, both antibodies were tested for binding to FGFR4 from four different species: human (hFGFR4), rhesus (rheFGFR4), rat (rFGFR4) and mouse (mFGFR4). As shown in FIG.18, h3A11-2 and c3A11 had similar binding affinities for hFGFR4 and rheFGFR4, but neither antibody bound to mFGFR4 or rFGFR4. The Kd and Bmax are summarized in Table 4. Table 4. One site binding nonlinear fit with Prism 8 Antibody+FGFR4 Kd Bmax 4239-111442-02Binding of c3A11 and h3A11-2 to human and rhesus FGFR4 proteins was also evaluated by BLI. Binding avidity was evaluated using a 1:2 binding model and global fitting analysis. The results are shown in FIGS.19A-19D. The dissociation constants (KD) for each binding interaction are shown in Table 5. Table 5. KD of 3A11 binding to human and rhesus FGFR4 by BLI Antibody Human FGFR4 Rhesus FGFR4 c3A11 67.18 pM <1 pM It will be apparent that the precise details of the methods or compositions described may be varied or modified without departing from the spirit of the described aspects of the disclosure. We claim all such modifications and variations that fall within the scope and spirit of the claims below.

Claims

4239-111442-02CLAIMS 1. An antibody-drug conjugate (ADC), comprising: a monoclonal antibody or antigen-binding fragment thereof that specifically binds fibroblast growth factor receptor 4 (FGFR4), comprising a variable heavy (VH) domain and a variable light (VL) domain, wherein the VH domain comprises the heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 sequences of SEQ ID NO: 11 or SEQ ID NO: 1, and the VL domain comprises the light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3 sequences of SEQ ID NO: 2; and (i) a drug comprising exatecan or an exatecan derivative conjugated to the antibody or antigen-binding fragment; or (ii) a drug comprising monomethyl auristatin E (MMAE) conjugated to the monoclonal antibody or antigen-binding fragment.

2. The ADC of claim 1, wherein: the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 are respectively set forth as SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 19, SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8; or the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 are respectively set forth as SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO:

8.

3. The ADC of claim 1 or claim 2, wherein: the amino acid sequence of the VH domain is at least 90% identical to SEQ ID NO: 1 and comprises the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 11 or SEQ ID NO: 1; and / or the amino acid sequence of VL domain is at least 90% identical to SEQ ID NO: 2 and comprises the LCDR1, LCDR2 and LCDR sequences of SEQ ID NO:

2.

4. The ADC of any one of claims 1-3, wherein: the amino acid sequence of the VH domain comprises or consists of SEQ ID NO: 1; and / or the amino acid sequence of the VL domain comprises or consists of SEQ ID NO:

2.

5. The ADC of claim 1 or claim 2, wherein the VH domain and the VL domain are humanized.

6. The ADC of claim 5, wherein: the amino acid sequence of the VH domain is at least 90% identical to SEQ ID NO: 11, SEQ ID NO: 13 or SEQ ID NO: 9; and / or4239-111442-02the amino acid sequence of the VL domain is at least 90% identical to SEQ ID NO: 12, SEQ ID NO: 14 or SEQ ID NO:

10.

7. The ADC of claim 5 or claim 6, wherein: the amino acid sequence of the VH domain comprises or consists of SEQ ID NO: 11, SEQ ID NO: 13 or SEQ ID NO: 9; and / or the amino acid sequence of the VL domain comprises or consists of SEQ ID NO: 12, SEQ ID NO: 14 or SEQ ID NO:

10.

8. The ADC of any one of claims 1-6, wherein the antigen-binding fragment is a scFv.

9. The ADC of claim 8, wherein the amino acid sequence of the scFv is at least 90% identical to SEQ ID NO: 16 or SEQ ID NO:

15.

10. The ADC of claim 8, wherein the amino acid sequence of the scFv comprises or consists of SEQ ID NO: 16 or SEQ ID NO:

15.

11. The ADC of any one of claims 1-7, wherein the monoclonal antibody or antigen- binding fragment further comprises at least one constant domain.

12. The ADC of claim 11, wherein the at least one constant domain comprises human CH1, CH2 and CH3 domains.

13. The ADC of claim 11, wherein the human CH1, CH2 and CH3 domains are human IgG1 CH1, CH2 and CH3 domains.

14. The ADC of claim 13, wherein the amino acid sequence of the CH1, CH2 and CH3 domains comprises or consists of SEQ ID NO:

17.

15. The ADC of any one of claims 11-14, wherein the at least one constant domain comprises or further comprises a human light chain constant (LC) domain.

16. The ADC of claim 15, wherein the human LC domain is a human IgG1 LC domain.

17. The ADC of any one of claims 1-16, wherein MMAE is conjugated to the monoclonal antibody or antigen-binding fragment via a linker comprising valine-citruline-p- aminocarbamate (VC-PABC).4239-111442-0218. The ADC of any one of claims 1-6 wherein the exatecan or exatecan derivative is conjugated to the monoclonal antibody or antigen-binding fragment via a linker comprising mpGlyAsnAsn, mpGlyAsnAsnGly, mpGlyAsnAsn(beta-Ala), or mpGlyAsnAsn(gamma- aminobutyric acid (GABA)).

19. The ADC of any one of claims 1-16 and 18, comprising:a or a or 20. A composition comprising the ADC of any one of claims 1-19 and a pharmaceutically acceptable carrier.

21. A method of treating a FGFR4-expressing cancer in a subject, comprising administering to the subject a therapeutically effective amount of the ADC of any one of claims 1-19 or the composition of claim 20.

22. A method of inhibiting tumor growth or metastasis of a FGFR4-expressing cancer in a subject, comprising administering to the subject a therapeutically effective amount of the ADC of any one of claims 1-19 or the composition of claim 20.

23. The method of claim 21 or claim 22, wherein the FGFR4-expressing cancer is a rhabdomyosarcoma (RMS), a lung cancer, a liver cancer, a breast cancer, a pancreatic cancer, a prostate cancer, a desmoplastic small round cell tumor (DSRCT), an adrenocortical carcinoma (ACC), or a gastric adenocarcinoma.

24. The method of claim 23, wherein the RMS is alveolar RMS (ARMS) or embryonal RMS (ERMS).4239-111442-0225. The method of claim 23, wherein the liver cancer is hepatocellular carcinoma (HCC) or hepatoblastoma (HBL).

26. The method of any one of claims 21-25, wherein the ADC is administered intravenously.

27. The method of any one of claims 21-26, wherein the subject is a human subject.

28. The method of any one of claims 21-27, wherein the subject is administered multiple doses of the ADC.

29. The method of claim 28, wherein the subject is administered two, three, four, five, six, seven or eight doses of the ADC.

30. The method of any one of claims 21-29, further comprising: administering to the subject an additional anti-cancer agent; performing surgery on the subject to resect a tumor; and / or subjecting the subject to radiation therapy.

Images