Antibody-drug conjugates (ADCs) enable cell-specific delivery of small molecules and are validated anti-cancer therapeutics. One factor limiting ADC advancement and broader application is the drug-to-antibody ratio (DAR), which dictates the number of payloads that can be delivered per antibody. With few exceptions, efficacious ADCs with DAR > 4 are inaccessible due to aggregation or rapid clearance in vivo. Here, we report a versatile platform for the generation of homogeneous ADCs with DAR up to 18, combining Cys-engineered THIOMAB antibodies and XTEN polypeptides to give “TXCs”. We show that high-DAR TXCs are stable biochemically and in vivo. We demonstrate that two different cytotoxic TXCs directed toward a tumor xenograft and one TXC targeting Staphylococcus aureus have comparable pharmacokinetics, but significantly enhanced efficacy in vivo versus conventional low-DAR ADCs. Our data suggest that high-DAR TXCs may ultimately offer several advantages versus conventional ADCs, including increased therapeutic index and efficacious delivery of less potent payloads.