As a novel CEA-directed therapy, we have developed a CEAtargeting bispecific single-chain antibody of the bispecific T-cell engager (BiTE) class termed MEDI-565 (also known as MT111) [16, 17, 18] . BiTE antibodies are a unique subclass of bispecific antibodies that contain one single chain variable fragment (scFv) with specificity for a tumor associated antigen molecularly fused to another scFv with specificity for CD3 on T cells [19] . Highly potent and specific tumor cell lysis is triggered only when BiTE antibodies bind both epitopes simultaneously, resulting in directing T cells to the tumor cells and activating the T cell through the CD3/T cell receptor (TCR) complex [20] . Notably, activation of T cells is independent of TCR specificity, peptide antigen presentation, and co-stimulatory signals [21] . As a result of T cell activation, granzymes and perforin are mobilized to the tumor cell-T cell interface and mediate an apoptotic killing of target cells; FAS ligand expression may also contribute to the induction of apoptosis through engagement of FAS on tumor cells [22, 23, 24] . BiTE antibodies activate both CD4+ and CD8+ T cell subsets [23, 25, 26, 27, 28] ; both subsets of T cells contribute to tumor cell killing at relatively low effector T cell:target tumor cell (E:T) ratios [22, 29] . Cytokine secretion and the upregulation of cell surface IL-2 receptor by T cells (measured experimentally using antibodies recognizing the IL-2Ra chain/CD25) occur simultaneously and accompany tumor cell killing [18, 22, 25] . Both potentiate further T cell activation and proliferation, facilitating the subsequent engagement and killing of additional tumor cells bound by a BiTE antibody. BiTE antibodies not only induce the potent lysis of human cancer cell lines in vitro, but have also been shown to mediate the killing of primary human tumor cells by cancer patient T cells ex vivo [17, 25, 30] . Furthermore, BiTE antibodies promote in vivo tumor regression in numerous pre-clinical animal models [16, 31, 32, 33, 34, 35, 36] and have shown signs of clinical benefit in patients with cancer [37, 38, 39] .