Abstract Antibody approaches that abrogate signaling from the HER2 or EGFR receptors have been proven effective in patients with breast or colorectal cancer, respectively. These antibodies do not have an effect however in colorectal patients with KRAS mutations or breast cancer patients that lack HER2 gene amplification as signal interruption is not sufficient to induce cell death. Here we identify several novel compounds that specifically recognize and kill HER2 and EGFR expressing cells irrespective of receptor signaling. These compounds were identified from a screen of a novel biologic library derived from a de-immunogenized Shiga-like toxin 1 A subunit (SLT1A); SLT1A has no intrinsic binding ability of its own but can drive internalization, retrograde transport to the cytosol, and enzymatic inhibition of ribosome activity. This modified library of engineered toxin bodies (ETBs) was created through the insertion of random amino acids near the C-terminus of the SLT1A scaffold to confer binding ability to SLT1A while preserving the therapeutic PK and ADME profile of the scaffold. HER2 and EGFR specific ETBs have been identified that exhibit potent cell-kill activity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1380. doi:10.1158/1538-7445.AM2011-1380