Ligand Drug Conjugates are provided having a DRS binding moiety attached via linking groups andor spacers to a therapeutic agent that are effective in treatment of various cancers. In some embodiments, the Ligand Drug Conjugate has the formula: L-(LU-D)p, where L is a Ligand unit, LU is a Linker unit and D is a Drug unit (or cytotoxic agent). The subscript p is an integer of from 1 to 20. Accordingly, the Ligand Drug Conjugates comprise a Ligand unit covalently linked to at least one Drug unit. The Drug units can be covalently linked directly or via a Linker unit (-LU-). The Ligand unit is a DR5 binding agent, such as an anti-DRS antibody.