The present invention provides cell-targeting molecules comprising binding regions for cell-type specific targeting and Shiga toxin A Subunit effector regions for Shiga toxin effector functions, wherein the Shiga toxin effector regions are at and/or proximal to an amino-terminus of a polypeptide component of the cell targeted molecule, and optionally comprising a disrupted, furin-cleavage motif between the Shiga toxin effector region and the binding region. The cell-targeting molecules of the invention exhibit a more optimized cytotoxicity and/or improved, in vivo tolerability as compared to related molecules comprising less amino-terminus proximal, Shiga toxin effector regions and/or furin-cleavage sensitive, wild-type, Shiga toxin effector regions. The cell targeting molecules of the invention have uses, such as, e.g., in methods involving targeted killing of cells, delivering exogenous materials into cells, labeling subcellular compartments of cells, and diagnosing and/or treating a variety of conditions, including cancers, tumors, other growth abnormalities, immune disorders, and microbial infections.
