Individual or combinations of somatic mutations found in genes from colorectal cancers can redirect the effects of chemotherapy and targeted agents on cancer cell survival and, consequently, on clinical outcome. Novel therapeutics with mechanisms of action that are independent of mutational status would therefore fulfill a current unmet clinical need. Here the CEA and CD3 bispecific single-chain antibody MEDI-565 (also known as MT111 and AMG 211) was evaluated for its ability to activate T cells both in vitro and in vivo and to kill human tumor cell lines harboring various somatic mutations commonly found in colorectal cancers. MEDI-565 specifically bound to normal and malignant tissues in a CEA-specific manner, and only killed CEA positive cells. The BiTE® antibody construct mediated T cell-directed killing of CEA positive tumor cells within 6 hours, at low effector-to-target ratios which were independent of high concentrations of soluble CEA. The potency of in vitro lysis was dependent on CEA antigen density but independent of the mutational status in cancer cell lines. Importantly, individual or combinations of mutated KRAS and BRAF oncogenes, activating PI3KCA mutations, loss of PTEN expression, and loss-of-function mutations in TP53 did not reduce the activity in vitro. MEDI-565 also prevented growth of human xenograft tumors which harbored various mutations. These findings suggest that MEDI-565 represents a potential treatment option for patients with CEA positive tumors of diverse origin, including those with individual or combinations of somatic mutations that may be less responsive to chemotherapy and other targeted agents.
Keywords: AMG 211; BiTE®, bi-specific T cell engager; CD3; CEA; CEA, carcinoembryonic antigen; CEACAM5, CEA-related cell adhesion molecule family member 5; DHFR, dihydrofolate reductase; EC50, half maximal effective concentration; FFPE, formaldehye fixed paraffin embedded; IV, intravenous; MEDI-565; MEDI-565, bispecific single-chain antibody specific for CEA and human CD3; MT111; SC, subcutaneous; SEM, standard error of the mean; T cells; TMA, tissue microarray; bispecific antibody; peripheral blood mononuclear cells, PBMC; scFv, single chain variable fragment.