An antibody-drug conjugate (ADC) consisting of a monoclonal antibody against the interleukin-3 (IL3)-receptor alpha chain (CD123; IL-3RA), conjugated, via a legumain-cleavable linker, to a physicochemically-modiffied payload composed of a kinesin spindle protein inhibitor (KSPi), with potential antineoplastic activity. Upon administration of anti-CD123/KSPi ADC VIP943, the antibody moiety targets the cell surface antigen CD123. Upon antibody/antigen binding, internalization, and transport to the lysosome, the KSPi moiety is released upon cleavage by the tumor-specific protease legumain, thereby accumulating the hydrophobic KSP (kinesin-5 or Eg5) inhibitor inside the tumor cell. In turn, KSPi inhibits KSP, thereby inhibiting mitotic spindle assembly, leading to an induction of cell cycle arrest during the mitotic phase, and cell death in CD123-overexpressing tumor cells that are actively dividing. This prevents proliferation of CD123-expressing tumor cells. KSP is an ATP-dependent microtubule motor protein that is essential for the formation of bipolar spindles and the proper segregation of sister chromatids during mitosis. CD123 regulates the proliferation, survival and differentiation of hematopoietic cells. CD123 is overexpressed on a variety of cancers, including myeloid leukemia, and increased expression of CD123 on leukemic stem cells is associated with poor prognosis. The modified KSPi payload is hydrophilic and thereby prevents diffusion out of the cell, allowing intracellular accumulation and reduces off-target toxicities by preventing membrane permeability into healthy cells.