Evaluation of efficacy and toxicity of carcinoembryonic antigen related cell adhesion molecule (CEACAM)6 targeted immunotherapy in pancreatic adenocarcinoma

4195 Carcinoembryonic Antigen Related Cell Adhesion Molecule (CEACAM)6, a glycosylphosphoinositol (gpI)-linked, cell surface member of the Carcinoembryonic Antigen (CEA) family of molecules, has been suggested as a potential target for immunotherapy in pancreatic adenocarcinoma. However, expression of CEACAM6 on an array of normal tissues, including myeloid cells, suggests the potential for antigen dependent toxicity, which can not be delineated in murine models because CEACAM6 has no murine ortholog. The aims of this study were to further characterize the expression of CEACAM6 in human tissues and on leukocytes of the peripheral blood (PB) and bone marrow (BM), and to determine the efficacy and antigen dependent toxicity of an anti-CEACAM6 directed immunoconjugate in relevant in vivo models. Using a murine monoclonal antibody (MAb) against CEACAM6 (Genentech, Inc.) we have expanded the characterization of CEACAM6 expression in human normal and malignant tissues, and PB and BM leukocytes, by immunohistochemistry (IHC) and fluorescence activated cell sorting analysis (FACS), respectively. Furthermore, we employed the antibody in unconjugated and maytansinoid (DM1)-conjugated forms to assess efficacy in a murine xenograft model and antigen dependent toxicity in non-human primates. CEACAM6 was expressed in 97% (65 of 67 cases) of ductal pancreatic adenocarcinoma by paraffin section IHC. In the PB and BM, CEACAM6 expression was limited to differentiated myeloid cells (CD33+, CD15+, CD13+, CD14+, CD116+). Myeloid lineage progenitor cells (CD34+/CD38+/CD33+) did not express CEACAM6, indicating that the immunoconjugate should not bind this population of regenerating cells. In a murine xenograft model of pancreatic cancer, the DM-1 immunoconjugate, but not the unconjugated anti-CEACAM6 MAb, caused tumor regression in a dose dependent manner. When administered to Cynomolgus macaques (single dose), the DM-1 immunoconjugate, but not the unconjugated antibody, conferred a decrease in absolute neutrophil count 7 days after dosing; staining of bone marrow smears from these animals with myeloperoxidase, a marker for myeloid cells indiscriminant of differentiation, showed that myeloid cells were present. In conclusion, CEACAM6 is expressed in a large proportion of ductal pancreatic adenocarcinomas as well as myeloid cells in PB and BM. CEACAM6 directed immunoconjugate therapy is efficacious in a murine xenograft model but more work is needed to fully characterize the antigen dependent toxicity, before such strategies can move forward.